OBESITY: A PUZZLING CVD RISK FACTOR

Although it is widely recognized that obesity presents challenges to

good health, physicians have always been puzzled by the heterogeneity
of CVD risk factors among obese patients. For instance, it is now
well documented that some massively obese patients are rather free
from major metabolic abnormalities (20,21), whereas some other
barely overweight individuals may be characterized by a whole constellation
of diabetogenic and atherogenic metabolic abnormalities
(22,23). Studies conducted over the past 25 years have shed light on
the reasons for such individual variation in the CVD risk factor profile
of overweight/obese patients. Such work has highlighted the remarkable
seminal work of Jean Vague from the University of Marseille,
who, in 1947, was the first to suggest that the regional distribution of

body fat was a more important correlate of the complications of obesity

than excess fatness (24). His initial theory, reported in a French
medical journal in 1947 (24) and then published for the first time in
the English literature in 1956 (25), was first received with curiosity
but with considerable skepticism by the scientific/medical community.
Although some reports published in the 1960s had suggested that
Vague could be right (26,27), it is really in the early 1980s that
Björntorp and Kissebah simultaneously reported convincing metabolic
and epidemiological data that confirmed the notion that the
proportion of abdominal fat was a key correlate of diabetogenic and
atherogenic metabolic abnormalities (28-31). For instance, the
Gothenburg prospective study of middle-aged men and women
showed that irrespective of the body mass index (BMI) (an anthropometric
index of total adiposity), an increased ratio of waist-to-hip circumferences
(as a crude index of relative abdominal fat deposition)
was predictive of an increased risk of ischemic heart disease and of
type 2 diabetes (29-31). Since this seminal work, which has spurred
considerable interest, numerous studies published the past 25 years
have confirmed the notion that a high proportion of abdominal fat
predicts cardiovascular events beyond the risk associated with excess
body fatness.
Recently, two large epidemiological studies (32,33) provided
robust additional evidence that it is important to assess abdominal adiposity
with the use of the waist circumference measurement as an
anthropometric index of abdominal fat deposition. The first study, the
International Day for the Evaluation of Abdominal obesity (IDEA)
(32), was a very large cross-sectional evaluation of approximately
170,000 patients seen by primary care physicians in 63 countries. The
6400 physicians who participated in the study were asked to measure
weight and height, and were also instructed on how to measure the
waistline of their patients. Then, they simply reported on the clinical
status of their patients. Results of IDEA clearly showed that primary
care physicians can learn how to properly measure waist circumference
when they are trained how to do it. Furthermore, IDEA provided
more evidence that waist circumference predicted CVD and diabetes
at any BMI level. Although the IDEA study was very large in size and
confirmed the clinical relevance of measuring waist circumference, it
had a cross-sectional design and only assessed the prevalence of diabetes
and CVD associated with abdominal obesity.
Recently, investigators of the European Prospective Investigation
into Cancer in Norfolk (EPIC-Norfolk) study reported the respective
relationships of waist and hip circumferences to incidence of coronary
artery disease (CAD) (33). EPIC-Norfolk is a large prospective study of
a population-based sample of 24,508 men and women 45 to 79 years of
age, who were followed for 9.1 years for incidence of CAD. The study
had considerable statistical power because 1708 men and 892 women
developed CAD over the course of follow-up. The authors reported that
an increased waist circumference was associated with an elevated CAD
risk, whereas a large hip girth appeared to protect against CAD after
adjustment for BMI, age, systolic blood pressure, cholesterol, cigarette
smoking, physical activity and alcohol intake.
The finding that waist circumference was a predictor of CAD incidence
was fully concordant with previous studies (32,34,35) that had
shown that an increase in waist circumference increases CAD risk at
any BMI level. In another landmark epidemiological study, INTERHEART
(36), which compared myocardial infarction patients with
asymptomatic controls, it was also reported that an increased proportion
of abdominal fat, as reflected by a high waist-to-hip circumference
ratio, was associated with a significant increase in the odds ratio
for myocardial infarction.
In EPIC-Norfolk, the investigators also performed a regression
analysis of waist circumference values against CAD risk and they estimated
that a 5 cm reduction in waist circumference could decrease
CAD risk by 11% in men and 15% in women (33). Interestingly, it
has generally been considered that a weight loss of 1 kg is associated
with a reduction in waist circumference of approximately 1 cm (33).
Thus, a weight loss of only 5 kg would therefore be enough to producethe reduction in CAD risk estimated by the EPIC-Norfolk
investigators
from a relatively small reduction in waist circumference. Of
course, intervention studies will be required to confirm these estimates,
but they are consistent with the well documented beneficial
effect of a 5% weight loss on the metabolic risk profile

Progress in reducing cancer death rates is evident whether measured against baseline rates in
1970 or in 1990. The downturn in cancer death rates since 1990 result mostly from reductions in tobacco use, increased
screening allowing early detection of several cancers, and modest to large improvements in treatment for specific cancers.
Continued and increased investment in cancer prevention and control, access to high quality health care, and research
could accelerate this progress.

Obesity, defined as a body mass index (BMI) >30 kg/m2, is a

significant health problem [1]. Obesity has reached epidemic
proportions globally, and the World Health Organization
estimates that there are more than 1 billion overweight
adults, of which at least 300 million are obese [2]. Societal
changes and the worldwide nutrition transition have driven
the obesity epidemic over recent decades. Economic growth
as well as modernization, urbanization and globalization
of food markets are some of the elements that have contributed
to the obesity epidemic. Significant shifts toward less
physically demanding work have been observed worldwide.
Decreased physical activity has also been associated with
increasing opportunities to use automated transport, have
technology in the home, and engage in more passive leisure
pursuits [2].
Obesity is associated with premature death through
increasing the risk of many chronic diseases, including
type 2 diabetes, cardiovascular disease, and certain cancers
(Figure 1) [3, 4]. In addition, obesity is associated with
respiratory difficulties, chronic musculoskeletal problems,
lumbago, skin problems, and infertility (Figure 1) [4].
Most of the evidence proposing obesity-associated health
problems has been obtained from epidemiological analyses
of human subjects; the precise molecular mechanisms of
obesity-associated health problems have not yet been determined.
In this paper, we will summarize reports associatedwith obesity-related pathology using animal models and
also propose further demand for animal research models to
address the worldwide obesity epidemic.
3.1. Diabetes and Obesity. Type 2 diabetes is associated
with insulin resistance and is one of the most common
metabolic diseases. The incidence of type 2 diabetes has
dramatically increased in the past two decades, coinciding
with the epidemic of obesity. The pathogenesis of insulin
resistance and diabetes-associated complications remains
unclear. Research on type 2 diabetes using animal models of
obesity is therefore quite significant.
Models of obesity with type 2 diabetes are classified
into two categories: (1) those containing a mutation in the
leptin or leptin receptor gene and (2) polygenic models.
Obese rodents, such as Zucker rats, ob/ob mice, and db/db
mice, are used as models for type 2 diabetes. Obesity in
these models is due to leptin signaling deficiency. These
rodent models exhibit microvascular complications similar
to humans, such as diabetic retinopathy and nephropathy,
and provide important models for testing experimental
therapeutics. However, leptin abnormalities only comprise a
minority of obesity/diabetes cases in humans [70–72] and are
not the same condition of type 2 diabetes that is a worldwide
epidemic.
Polygenic models of obesity with diabetes may provide
more insight to the human condition. Certain inbred strains
of mice exhibit remarkable obesity when fed on HFD,
whereas others remain lean [48, 49, 73], suggesting genediet
interactions. Furthermore, some of the strains exhibit
obesity with severe insulin resistance and glucose intolerance,
whereas others are highly sensitive to insulin-mediated
glucose uptake and are resistant to the onset of diabetes
(Table 1) [50, 74, 75]. In contrast, some strains are very prone
to type 2 diabetes but not severely obese. Those polygenic
models allow for analysis of diabetic phenotypes alone, or
the mice can be fed on HFD or crossed with another obesity
mouse model, such as ob/ob, db/db, or Ay (Table 1) [50, 74,
75].
3.2. Cancer and Obesity. Obesity in humans is associated
with the incidence of several cancers. Likewise, type 2
diabetes has been associated with an increased risk of cancer.
Severalmechanisms have been proposed to explain the interaction
between obesity and cancer development, including
the prevalence of type 2 diabetes, increased insulin resistance,
elevated levels of insulin-like growth factor 1 (IGF-1),
and increased production of sex steroid hormones and
adipocytokines [76–80]. However, clear molecular mechanisms
that explain obesity-associated cancer have yet to be
determined. Recently, Park et al. reported a breakthrough
observation in carcinogenesis in obesity [81]. They found
that diethylnitrosamine-induced HCC is significantly higher
in both genetically (ob/ob) and HFD-induced (59% fat, 15%
protein, 26% carbohydrates) obese mice [81]. Furthermore,
HFD induced the growth of subcutaneously injected HCC,
suggesting that obesity has a systemic effect on tumorigenesis
[81]. With regard to the mechanisms of tumorigenesis in
obesity, they found that obesity is associated with increased
intracellular transcriptional factor STAT signaling and liver
inflammation [81]. This inflammation was demonstrated
to be essential for the tumor promoting effects of obesity
because the depletion of signaling by inflammatory cytokines
IL-6 and TNF-α abolished the tumor promoting effects of
obesity [81].
Metformin belongs to the biguanide class of antitype
2 diabetic drugs. Since the middle ages, the biguanide
Galega officinalis (goat’s rue or French lilac) has been used
to treat diabetic patients. Accumulating evidence suggests
that metformin reduces cancer incidence in type 2 diabetic
patients. Metformin activates AMPK and inhibits the

We have summarizedmany current animal models of obesity

and obesity-associated human diseases. However, animal
models have not yet been established for some devastating
obesity-associated human diseases, including polycystic
ovary syndrome [117, 118], which is extremely prevalent
and constitutes one of the most common endocrinopathy
in women of reproductive age. Suitable animal models are
fundamental to testing novel therapeutic strategies against
disease. Therefore, intensive and continuous efforts should
be made to establish novel obesity-associated animal models
that mimic human health problems.

The dramatic increase in the prevalence of obesity and its strong association with cardiovascular
disease have resulted in unprecedented interest in understanding the effects of obesity on the
cardiovascular system. A consistent, but puzzling clinical observation is that obesity confers an
increased susceptibility to the development of cardiac disease, while at the same time affording
protection against subsequent mortality (termed the obesity paradox). In this review we focus on
evidence available from human and animal model studies and summarize the ways in which
obesity can influence structure and function of the heart. We also review current hypotheses
regarding mechanisms linking obesity and various aspects of cardiac remodeling. There is
currently great interest in the role of adipokines, factors secreted from adipose tissue, and their
role in the numerous cardiovascular complications of obesity. Here we focus on the role of leptin
and the emerging promise of adiponectin as a cardioprotective agent. The challenge of
understanding the association between obesity and heart failure is complicated by the multifaceted
interplay between various hemodynamic, metabolic, and other physiological factors that ultimately
impact the myocardium. Furthermore, the end result of obesity-associated changes in the
myocardial structure and function may vary at distinct stages in the progression of remodeling,
may depend on the individual pathophysiology of heart failure, and may even remain undetected
for decades before clinical manifestation. Here we summarize our current knowledge of this
complex yet intriguing topic.

1. Quantification of cardiac hypertrophy in obesity—Cardiac hypertrophy is usually

defined as an increase in the size of the entire heart or more commonly of a specific cardiac
chamber relative to body size. In the past, body surface area (BSA) was often chosen as the
index of body size against which to judge cardiac size or mass. However, in the setting of
significant obesity, LV weight/BSA is often normal or lower than normal because BSA
increases more than LV weight (72,73,197). Because of this, many investigators now choose
to index heart size to lean body mass, height, or height raised to the power of 2.7 (72,73).
The latter method is proposed to be an optimal allometric correction factor that minimizes
gender differences in cardiac size and geometry (70). Commonly accepted cut-off values for
increased LV mass are >50 g/m2in men and 47 g/m2.7in women (72,197).
2. Patterns of LVH in obesity—Many published studies have concluded that obesity is
independently associated with LV hypertrophy (22,28,63,72,116,235,242,266,279,284,377). A
few studies suggest that LV mass may be increased in obesity, but that the increase is
appropriate for body size if obesity is truly “uncomplicated” (i.e., lack of comorbid
conditions such as hypertension, diabetes, coronary artery disease, etc.) (151,155,156).
There are somewhat divergent views about the degree of hypertrophy and the particular LV
geometric patterns that are seen in obesity. Early studies in relatively small numbers of

3. Cardiac tissue composition in obesity—Relatively few studies have compared the

biochemical and structural composition of the heart in obese and normal subjects. This is not
too surprising given the large obstacles inherent in obtaining human cardiac tissue,
particularly from control subjects without organic heart disease. Thus we have largely been
forced to rely on data from animal models that may not accurately reflect the human
condition (see below). However, autopsy series present the opportunity to study heart tissue
from obese and nonobese subjects, and in general, these studies have shown cardiac
hypertrophy plus a variable extent of coronary artery disease (9,64,91,147,185–188,300).
However, studies relying on autopsy may be biased towards the presence of coexisting
conditions and/or unexpected causes of death.
4. Cardiac adiposity—Increased cardiac mass has been postulated to result from
increased epicardial fat and fatty infiltration of the myocardium (11). It is doubtful whether
excess epicardial fat should be considered as a true form of cardiac hypertrophy. However,
in autopsy studies, it might be difficult to separate adherent and infiltrating fat from
underlying cardiac muscle. Most imaging methodologies such as echocardiography and MRI
can now allow a relatively clear separation of myocardium from fat and allow calculation of
a “fat free” cardiac mass. Not surprisingly, increased epicardial fat is a common finding in
severe obesity. Iacobellis and colleagues (152,155) have argued that the amount of
epicardial fat parallels the amount of visceral adipose tissue and that the amount of
epicardial fat is correlated with the severity of LVH. Some authors have reported that
epicardial fat may penetrate into the right ventricular (RV) free wall and cause replacement
of RV myocardium (327). However, widespread use of cardiac MRI and computed
tomography, particularly when evaluating for possible arrhythmogenic right ventricular
dysplasia, have revealed that epicardial fat anterior to the right ventricle is extremely
common (178,342,344). Moreover, epicardial fat commonly interpolates into the RV free
wall. An example of a cardiac MRI showing a moderate accumulation of epicardial fat is
seen in Figure 2. One study used MRI spectroscopy to quantify triglyceride content in
human myocardium and found it to be significantly increased in obese compared with
normal-weight subjects (152). This observation is supported by the findings of Peterson etal. (278) who showed that
obese subjects, particularly those with insulin resistance, have
increased myocardial fatty acid uptake and utilization (278). Using a different approach,
Kasper et al. (170) performed endomyocardial biopsy to assess myocardial histology, and
obese subjects were found to have mild myocyte hypertrophy but no evidence of abnormal
collagen accumulation. In contrast, Quilliot et al. (288) reported that serum markers thought
to reflect cardiac collagen turnover were increased in obese subjects. Taken together, there
does not appear to be a specific pathological change in the human heart which is clearly
associated with obesity, other than mild myocyte hypertrophy and perhaps intra- and
extracellular fat accumulation.
5. Right ventricular size in obesity—A few studies have focused on the right ventricle
in uncomplicated obesity. Wong et al. (378) reported that RV cavity size and wall thickness
were mildly increased in obese subjects compared with a normal-weight reference group.
Alpert and co-workers (16,17) reached similar conclusions. Although it seems likely that
RV enlargement could result from obstructive sleep apnea and chronic pulmonary
hypertension (see below), the available published data surprisingly do not consistently
support this hypothesis (266,378). In fact, in one study the majority of obese subjects did not
have enough tricuspid valve regurgitation to even estimate pulmonary artery pressures, and
those that did have tricuspid regurgitation generally had normal pressures (378).
6. Left atrial size in obesity—Many studies have shown increased LA dimensions in
obese subjects compared with normal-weight control subjects (16,17,22,140,274,371,375).
Unlike LV mass, LA size is usually not indexed to body size, so this finding could be
misleading. The most commonly reported measure of LA size is the uniaxial anteriorposterior
dimension, which is generally measured from the parasternal long axis
echocardiographic view. This is a well-accepted, reproducible measure of LA size that has
known clinical relevance with respect to long-term event rate, survival, and the risk of
developing atrial fibrillation (114,180). The mechanisms of increased LA size appear to be
similar to those causing LVH: increasing BMI, hypertension, volume overload, and possibly
LV diastolic filling abnormalities. Interestingly, obese subjects in the Framingham heart
study were found to have an increased risk of developing atrial fibrillation, and this risk was
entirely explained by the increase in LA size (371).
7. Valvular heart disease in obesity—Only limited data exist regarding the direct
effects of obesity on the heart valves. Nevertheless, the topic of valvular disease in obesity
has received increased attention in recent years because of the finding that anorexigenic
drugs used to facilitate weight loss are associated with mitral and aortic valve regurgitation
(57). Somewhat counterintuitively, a widely cited paper that evaluated the frequency of
valvular abnormalities in a relatively large cohort of subjects undergoing echocardiography
showed a lower prevalence of valvular regurgitation in obese than in normal-weight subjects
(323). The problem of difficult echocardiographic imaging windows in obese subjects
complicates the quantitative assessment of valvular disease in this population.

Obesity and Atherosclerotic Coronary Artery Disease

There are multiple mechanisms by which obesity leads to atherosclerotic coronary artery
disease. First, obesity is associated with multiple factors which are themselves major risk
factors for atherosclerosis, including abdominal obesity, insulin resistance (and its ultimate
form, type 2 diabetes), atherogenic dyslipidemia (i.e., high plasma triglyceride and low highdensity
lipoprotein [HDL]-cholesterol concentrations), and hypertension. These risk factors
often cluster in what has been termed the “metabolic syndrome.” There is considerable
controversy as to whether the metabolic syndrome itself is a distinct risk factor for CVD, or if
it simply confers the risks associated with its parts. However, it is helpful to recognize that
separate components of the metabolic syndrome often accompany obesity and may cluster
together (Table 1). The metabolic syndrome is associated with increased risk of death from
CVD even in the subset of patients without frank diabetes. In one large study, the overall hazard
ratios for CVD mortality in those with metabolic syndrome were 2.26 and 2.78 in men and
women, respectively [4]. This increased risk of cardiovascular and coronary heart disease in
patients with the metabolic syndrome has been validated in at least 2 other large-scale trials
[5].
Obesity and hypertension
One of the components of the metabolic syndrome that often tracks with obesity, and which is
also a risk factor for CV disease, is hypertension. Data from population studies suggest that
approximately 75% of hypertension can be attributed to obesity [6]. On average, for each
increase of 10 kg of body weight there is an associated increase of 3.0 mmHg systolic and a
2.3 mmHg of diastolic blood pressure [7]. Although these blood pressure increases may at first
appear minor they portend a 12% increase in coronary heart disease risk and a 24% increase
in stroke risk [7].
The exact mechanisms for the relationship between obesity and hypertension are not
completely understood, but it is known that adipose tissue can make angiotensinogen,
angiotensin converting enzyme (ACE), and angiotensin receptor 1 (AT 1) [8,9]. Renin activity
and aldosterone are also upregulated in obesity [10]. These alterations increase plasma volume
and contraction of vascular smooth muscle, both of which may contribute to increased blood
pressure. Obesity is also associated with an imbalance sympathovagal system, as shown by
ganglionic nerve studies, heart rate variability studies, and renal norepinephrine spillover
studies [11]. This increased activation of the sympathetic nervous system may also contribute
to increased blood pressure in the setting of obesity due to the activation of β1-adrenoreceptors
in the myocardium, leading to an increased left ventricular (LV) dP/dt (rate of rise of LV
pressure). Increased sympathetic tone associated with obesity also may increase blood pressure
via arterial vasoconstriction due to alpha1-adrenoreceptor stimulation. Lastly, obesity is
associated with a low-grade systemic inflammatory state. Adipose tissue itself can manufacture
the proinflammatory cytokines, interleukin-6 (IL-6), and tumor necrosis factor- α (TNF-α), and
these can regulate other markers of inflammation, such as C-reactive protein (CRP) [12]. Data
are now emerging that link this increased inflammation with increases in blood pressure [13].
Based on these mechanisms, treatment of obesity with weight loss is recommended as a first
step by the 7th report of the Joint National Committee (JNC) on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure
(http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf). Weight loss is associated
with an improvement in hypertension in a dose-dependent fashion [14]. For patients without
other compelling indications, thiazide-type diuretics, ACE inhibitors, AT1 receptor blockers,
and β-adrenergic blockers are also rational therapies to consider in the obese patient with
hypertension based on the mechanisms described above, and all are listed as initial therapies
for Stage 1 hypertension per the 7th JNC report.

Obesity and dyslipidemia

Dyslipidemia is another classical risk factor for CVD that often tracks with obesity, especially
in obese patients who also have the metabolic syndrome. High triglycerides and low levels of
high-density lipoprotein (HDL) levels are commonly seen with obesity. Low HDL is a risk
factor for CVD in addition to the more commonly known lipid risk factor – increased lowdensity
lipoprotein (LDL). Although there is more controversy regarding the cardiovascular
risk associated with high triglycerides, there are now several large trials suggesting that they
are a risk factor for CVD, particularly in women [15,16]. The increase in triglycerides appears
to be at least in part due to an increase in fatty acid (FA) turnover and delivery to the liver
resulting in an increase in very low-density lipoprotein (VLDL) production [17]. Insulin
resistance (often accompanying obesity) lowers HDL levels partly due to increased
apolipoprotein A-1 (a component of HDL) catabolism and HDL remodeling from increased
hepatic lipase action [18]. HDL production from remnant particles of triglyceride-rich
lipoproteins is also hindered by insulin resistance [19]. The fact that these lipid abnormalities
(high triglycerides and LDL, and low HDL) generally improve with weight loss, further
supports the idea that obesity is directly involved in the development of this particular type of
atherogenic dyslipidemia [20].
Obesity and diabetes
There is no question that obesity is a risk factor for the development of type 2 diabetes, which
in turn is one of the most virulent of CV risk factors. Although not all persons who are obese
develop diabetes, almost 90% of patients with type 2 diabetes are at least overweight
(www.naaso.org/information/diabetes_obesity.asp). Unfortunately, diabetes is associated with
a markedly increased risk of CVD, such that it is the number one cause of death of persons
with diabetes. Moreover, it is well established that there are sex-related differences in the
manifestation of CVD in patients with diabetes, with women having a greater risk than men
[21].
The mechanisms by which obesity contributes to diabetes, and hence CVD risk, are the subject
of much research. Recent data suggests that adipose tissue is not simply an inert depot for
excess calories but is metabolically active. It generates and exports inflammatory markers,
hormones, and FAs that interact with other tissues. In particular, adipocytes appear to have a
stress response to excess lipid, which causes the endoplasmic reticulum (the locus of protein
production and folding) to undergo what has been termed the “unfolded protein response.”
This response impairs insulin signaling, and hence insulin resistance, and, if prolonged, may
result in apoptosis [22]. This process has also been implicated in the death of the insulinproducing
pancreatic beta cells, which may also contribute to the development of type 2
diabetes. Studies in animal models also demonstrate toxic effects of elevated FA levels on beta
cells (and other nonadipocytes) via a pathway known as “lipotoxicity” [23,24]. These pathways
provide intriguing targets for future therapeutic interventions, in addition to the more traditional
weight loss (discussed below) for the amelioration of obesity-related diabetes.
Obesity and endothelial function
Although not considered a traditional “risk factor” for the development of CVD, per se,
endothelial dysfunction is an early marker of CVD and contributes to CV events. The vascular
endothelium releases vasoactive relaxing and contracting factors that are important for the
control of vascular tone. An imbalance in the factors controlling vascular tone may lead to
vasoconstriction, vascular inflammation, thrombosis, and atherosclerosis. Increasing BMI
predicts impaired endothelial function [25]. It is particularly prevalent in patients with visceral
obesity and insulin resistance [26]. Unfortunately, the association between excess weight and
endothelial dysfunction can present as early as childhood [27]. Obesity is thought to affect endothelial function
predominately via co-morbidities, such as
insulin resistance and dyslipidemia. Supporting this is the observation that obese individuals
exhibit resistance to the vasodilator actions of insulin [28]. Furthermore, hyperglycemia and
hyperlipidemia, often present in obesity, have been shown to impair nitric oxide (NO)-induced,
endothelial-dependent vasodilation [29,30].
However, adipose tissue itself also appears to play an important role in the control of endothelial
function because adipocytokines have vasoactive properties [31]. For example, adiponectin
can accumulate in the vessel wall, exert anti-inflammatory effects, and enhance production of
NO [32]. Unfortunately, obesity is associated with relative adiponection deficiency, which thus
may contribute to impaired endothelial function. Leptin’s effects are more complicated since
some studies demonstrate it enhances sympathetic tone while increasing NO production, and
others show it improves endothelial- and NO-independent vasodilation [33,34]. Other
cytokines from adipocytes, IL-6, FAs, are thought to decrease NO production and so, contribute
to impaired endothelial function. Lastly, adipose-derived components of the renin-angiotensin
system also contribute directly to vasoconstriction [35,36].
Obesity and atherosclerosis
A thorough review of the entire atherosclerotic process is beyond the purview of this review
and has been described by Libby and others; however, in order to demonstrate obesity’s effect
on atherosclerosis, we will briefly outline the major events of atherosclerosis here [37]. One
of the earliest events of atherosclerosis is endothelial damage and dysfunction [38]. Also early
on, there is recruitment of blood monocytes, which attach to the endothelium via vascular cell
adhesion molecule (VCAM)-1 and migrate to the subendothelial space of the artery wall, where
they become tissue macrophages [37]. Low-density lipoprotein (LDL)-cholesterol also
migrates into the subendothelial space and is modified by oxidation or glycation [37]. This
modified LDL is then taken up by the scavenger receptors of the macrophages. Accumulation
of lipid within the macrophages creates the “foam cell” – the hallmark of the early
atherosclerotic plaque [37]. Foam cell breakdown, deposition of free cholesterol and its esters,
smooth muscle cell proliferation, and deposition of calcium and collagen occur in the later
stages of atherosclerosis [37]. Destabilization of the plaque via macrophage-derived matrix
metalloproteinases contribute to plaque rupture that precedes thrombosis and infarction [37].
All of the other CV risk factors that track with obesity contribute to this process, and so obesity
contributes to atherogenesis indirectly by contributing to these other risk factors.
Obesity also directly contributes to atherogenesis via the effects of some of the adipokines that
adipose tissue generates. Specifically, interleukin-6 (IL-6), tumor necrosis factor (TNF)-α,
angiotensin-II, and leptin, are all proinflammatory and are secreted by adipose tissue. IL-6
induces VCAM-1 expression and monocyte chemoattractant protein −1 secretion by
endothelial cells, both of which encourage monocytes to attach to and infiltrate into the
subendothelial space of the artery wall [7,37,39]. However, the effects of IL-6 on
atherosclerosis are complex and not simply pro-atherosclerotic since results from studies in
IL-6 murine knock-out models demonstrate that baseline, physiologic level of IL-6 may be
necessary for normal vascular development and modulation of vascular remodeling [40].
Another inflammatory adipokine, TNF-α, also stimulates VCAM-1 expression, LDL uptake
by macrophages, and promotes plaque destabilization [37,41,42]. Angiotensin II also
stimulates VCAM-1 and MCP-1 expresssion, monocyte infilitration, and smooth muscle cell
proliferation in the vessel wall [37]. Leptin also promotes atherosclerosis because leptin
increases the accumulation of cholesterol esters in foam cells and promotes oxidative stress
[43]. Adiponectin, an anti-inflammatory adipokine, on the other hand, is thought to stabilize
atherosclerotic plaques via tissue inhibitor of metalloproteinase-1 (TIMP-1), inhibit
transformation of macrophages to foam cells, and inhibit cell proliferation stimulated byoxidized LDL [36]. Thus,
the relative adiponectin deficiency associated with obesity also
would promote atherogenesis and plaque formation. Inflammation and oxidative stress also
appear to play a role in the vascular calcification that often is a relatively late finding in
atherosclerosis [44]. Thus, pro-inflammatory adipokines may also affect this pathologic
calcification process. In sum, obesity acts both indirectly and directly on the vasculature
promoting atherosclerosis, one of the main pathophysiologic processes leading to coronary
artery disease and its clinical sequelae.
Obesity and thrombosis
The final common event for most patients who have a myocardial infarction from
atherosclerotic coronary disease is endothelial lining rupture and subsequent thrombosis,
superimposed on an intracoronary plaque. Obesity is considered a prothrombotic condition due
to increased activity of the coagulation cascade, which is not fully compensated by increased
activity of the fibrinolytic cascade. Several studies have shown that the plasma concentrations
of many prothrombotic factors (fibrinogen, vonWillebrand factor [vWF], factor VII, and
plasminogen activator inhibitor-1 [PAI-1]) are higher in obese compared with normal weight
individuals [26,45]. Plasma concentrations of antithrombotic factors, such as tissue-type
plasminogen activator (t-PA) and protein C, are also increased, but not enough to counteract
the increase in prothrombotic factors [45].
The increased thrombotic potential accompanying obesity is related, at least in part, to insulin
resistance. Insulin resistance is associated with inflammation and oxidative stress, both of
which are implicated in the generation of components of the thrombotic cascade. Resistance
to insulin leads to thrombosis promotion because insulin is antithrombotic and profibrinolytic,
suppressing 1) NF-κB binding activity, 2) reactive oxygen species generation, 3)
proinflammatory factors expression, and 4) PAI-1, tissue factor, and platelet activity [46].
Excessive adipose tissue also directly contributes to the imbalance between thrombosis and
fibrinolysis because adipose tissue secretes multiple adipokines, cytokines, and hormones that
are implicated in thrombosis. Leptin, resistin, PAI-1, tissue factor, angiotensin II, FAs, TNF-
α, transforming growth factor-β, and IL-6 are all secreted by adipose tissue and are all
implicated in thrombosis [26,45]. The general pathway through which these adipokines are
thought to increase thrombotic potential is via inflammation and reactive oxygen species,
which are known to lead to platelet activation and thrombosis [26]. Weight loss has been shown
to improve this thrombotic tendency. Whether antioxidants have a beneficial effect on obesityrelated
thrombosis in humans is as yet unproven. Thus, obesity contributes indirectly to
atherosclerotic CVD via increasing the incidence of other CV risk factors, and obesity
contributes directly to atherosclerotic CVD via promoting atherogenesis and thrombosis.
Obesity and heart failure
Although obesity is a risk factor for coronary artery disease, and hence, ischemic
cardiomyopathy, obesity is also a risk factor for nonischemic heart failure. Rarely, obesity is
related with a pathologic condition, known as “Adipositas Cordis” wherein the myocardium
is so filled with lipid that it actually floats in water [7]. The lipid in the heart can be from an
infiltrative process, with adipocytes strands streaming in from the epicardial fat, and/or a
metaplastic process in which myocardial cells are replaced by adipocytes [7]. However, even
in obese subjects without this extreme pathologic phenotype, there are alterations in cardiac
structure, function, and metabolism that are characteristic of obesity, which may all contribute
to the development of heart failure. Obesity and cardiac structure
Recent studies, using modern techniques to evaluate cardiac structure suggest that obesity,
even in the absence of hypertension, first leads to concentric left ventricular remodeling,
characterized by increased LV wall thickness relative to the LV end-diastolic dimension. This
is best expressed as an increase in relative wall thickness (= 2 × posterior wall thickness/LV
end-diastolic dimension) and can be seen even in adolescents with obesity (Figure 1) [47]. In
support of this concept, BMI was the only independent predictor of LV mass and relative wall
thickness in 51 young women in a multivariate analysis [48]. These changes may be adaptive
and perhaps initially represent a beneficial response to obesity; i.e., by increasing wall
thickness, LV wall stress may be lessened. However, over time this adaptation likely becomes
maladaptive since frank LVH may ensue, which is an independent risk factor for sudden cardiac
death and is associated with diastolic and systolic dysfunction. Concentric LV hypertrophy is
thought to develop into eccentric hypertrophy with increased duration of obesity, and
consequent increased duration of LV volume overload [10]. This structural change from
concentric to eccentric LV hypertrophy with its defining LV cavity enlargement often
accompanies frank LV systolic failure [10]. Furthermore, systemic hypertension, which often
accompanies obesity, facilitates development of LV dilatation and hypertrophy [10]. Increased
LV mass also makes the subendocardium more susceptible to ischemia and increases the risk
of sudden cardiac death [10].
Obesity and cardiac function
There is evidence that excess body weight itself, independent of other known cardiovascular
risk factors and independent of atherosclerosis and myocardial infarction impairs both diastolic
and systolic function [48,49] Indeed, the risk of developing clinical heart failure is estimated
to increase by 5% −7% for every 1 kg/m2 BMI increase and is thought to contribute to 11–
15% of all heart failure cases [3]. Consistent with this there are several studies using loaddependent
measures demonstrating the detrimental effects of excess body weight on diastolic
function as measured using traditional echocardiographic Doppler imaging [50–53]. There is
also evidence that there are direct, load-independent effects of obesity on cardiac function. For
example, in a cross-sectional study of obese nonhypertensive, nondiabetic young women,
tissue Doppler measurements of diastolic function, which are thought to be relatively loadindependent,
were decreased as BMI increased [48].
The effects of obesity on LV systolic function are less clear-cut, with some studies
demonstrating decreased, some showing increased, and some showing no effect on LV systolic
function [48,53,54]. Part of the explanation for these discordant results is likely due to the loaddependent
nature of many of the measurement methods, since an obesity-related increase in
plasma volume may increase cardiac output via the Frank-Starling mechanism. Another reason
for the difficulty in assessing LV systolic function in obesity lies in the methods for indexing
it to body size. Thus, although stroke volume and cardiac output are often high in obesity, when
they are indexed to body surface area, they may be high, normal, or low. To assess contractility
in a more load-independent manner, we evaluated the tissue Doppler measure of systolic
function, Sm, in young women with uncomplicated obesity and found that systolic function
was worse as BMI increased [48]. Thus, the mechanisms responsible for the obesity-related
impairment in heart function appear due to both alterations in load (volume and pressure) as
well as load-independent alterations. There is an increase in load through an increase in plasma
and blood volume via activation of the renin-angiotensin-aldosterone system [10]. Pathologic
and calibrated integrated backscatter studies also suggest that there are textural alterations in
the myocardium that may affect the viscoelastic properties of the myocardium, which may be
load-independent [49]. Lastly, alterations in myocardial metabolism may also play a role in
the development of cardiac dysfunction. Obesity and myocardial metabolism
Animal studies suggest that alterations in myocardial metabolism contribute to cardiac
dysfunction in obesity [23,55]. Normally, the myocardium is an omnivore, able to utilize
multiple substrates for metabolism but in the postnatal, resting, fasted state it primarily uses
FAs. In response to an increase in FA delivery, the myocardium typically increases betaoxidation
of FAs (Figure 2). This increase in beta-oxidation of FAs occurs in animal models
of obesity, even before the onset of diabetes [56]. However, it appears that if excessive FA
delivery to the myocardium persists, even the myocardium’s great capacity for FA oxidation
may be overwhelmed leading to increased FA storage (Figure 2). Although much of this excess
lipid may be stored in a relatively neutral form such as triglycerides, some of the FAs that enter
the cell may contribute to apoptosis, via lipotoxicity [23]. Studies in animal models show that
lipotoxicity may occur via ceramide-dependent or –independent pathways [23,24]. In these
animal models of lipotoxicity, the myocardial metabolic abnormalities precede cardiac
dysfunction and are thought to contribute to it [23,55,57]. Whether this process also occurs in
humans is the subject of intense investigation.
In a study of young women with uncomplicated obesity, our group found that myocardial FA
upake, utilization, and oxidation all were increased as BMI and whole body insulin resistance
increased, paralleling what was found in animal models of obesity [56,58]. It appears that this
increased FA oxidation capacity in humans may also be overwhelmed, as it can be in animal
models because autopsy and magnetic resonance spectroscopy studies both demonstrate that
in subjects with diabetes there is an increase in intramyocellular triglyceride compared with
normal controls [59]. In addition, LV biopsies from human hearts undergoing LV assist device
implantation for heart failure demonstrate that patients with obesity or diabetes and heart failure
have more accumulation of lipid within the myocardium than those with heart failure from
other causes [60]. Also more indirectly supporting the theory that excessive FAs may contribute
to LV dysfunction in obesity are results from a study relating plasma free FAs an LV diastolic
dysfunction [61]. Further studies, including longitudinal and interventional studies are still
needed in humans to prove that lipotoxicity occurs as it does in animal models.
Excessive myocardial FA metabolism may also contribute to cardiac dysfunction via increased
free radical production. In obesity, with its inherant increase in FA oxidation, there is increased
myocardial oxidative stress [62]. In animal studies free radicals appear to impair both vascular
and LV systolic and diastolic function since decomposition of free radicals lead to improvement
of these parameters [63]. Supporting this theory that not all of the cardiac dysfunction that is
seen with obesity is due to apoptosis-related injury, are studies showing improvement in cardiac
function after significant weight loss [64,65]. If myocardial cell loss were the only mechanism
by which cardiac function were decreased, it would be unlikely to improve after weight loss.
Lastly, increasing BMI is an independent predictor of increasing myocardial oxygen
consumption and decreasing efficiency both in animal models and in a recent study in young
obese women [58,66]. Decreased efficiency may contribute to impaired ATP production,
thereby hindering cardiac function, and decreased efficiency is a hallmark of heart failure.

EFFECT OF CHILDHOOD AND ADOLESCENT OBESITY

As noted earlier, obesity during the teen years is associated
with many adverse health consequences (see discussion below),
which include greater rates of mortality as young adults (22).
The adolescent years are a time of change in body composition,
as well as changes in insulin sensitivity and in concentrations of
the adipokines (chemicals produced by the fat cell) such as
leptin and adiponectin. Puberty is associated with increases
in lean body mass as well as fat mass, with a greater increase in
fat mass in girls compared with boys (49). Girls experience
a greater increase in fat mass throughout childhood and puberty
than boys, and heavier girls experience a greater increase in fat
mass during puberty than other girls (50–53). There is a rise in
insulin resistance during puberty (54, 55), as well as a worsening
of various components of the metabolic syndrome, and concurrently,
changes in leptin and adiponectin (56–58). However,
pubertal changes in leptin are sex-dependent, and increased
concentrations of androgens in males can lead to a decrease in
leptin concentrations (59). As previously described, the likelihood
of an obese child becoming an obese adult increases with
the age of the child independently of the duration of time that
the child has been obese (16–18). Childhood obesity is associated
with earlier pubertal maturation in girls, and early maturing
girls tend to have higher BMIs and body fat at the time of
menarche (36, 60–66). However, most girls increase their body
fat as they progress through puberty, and therefore a causal relation
has not been established. A longitudinal study noted that
adult obesity was more strongly associated with childhood
obesity than with the timing of puberty (67), which suggests that
childhood obesity is the underlying factor for both age of onset
of puberty and adult obesity.
Many of the comorbidities associated with obesity are related
to several abnormal anthropometric and metabolic changes that
tend to cluster and are termed the metabolic syndrome (68).
Several definitions have been proposed for the metabolic syndrome
in adults; the 2 most commonly used definitions in
children and adolescents are modified from the adult criteria and
may include the criteria of insulin resistance and type 2 diabetes.
The definitions proposed by Cook et al (69) define metabolic
syndrome as the presence of _3 criteria that include elevated
triglycerides (.110 mg/100 mL), low HDL (,40 mg/100 mL),
abdominal circumference .90th percentile by sex, elevated
fasting glucose (.110 mg/100 mL), and high blood pressure
(.90th percentile). The criteria proposed by de Ferranti et al
(70) uses _3 of 5 criteria: high blood pressure (.90th percentile
for age, sex, height), central obesity (waist circumference .75th
percentile for age and sex), low HDL (1.3 mmol/L in girls), high
fasting glucose (.6.1 mmol/L), and hypertriglyceridemia (.1.1
mmol/L). These definitions, although similar, lead to slightly
different outcomes.
Abdominal obesity is the most commonly observed metabolic
syndrome phenotype, the one best correlated with other metabolic
syndrome phenotypes (71) and the most predictive of the
risk of developing the syndrome in children over a 15 y period
(72). Thus, it is likely that abdominal obesity that promotes
insulin resistance is the most central factor underlying the
metabolic syndrome in genetically predisposed individuals due to
the increased flux of free fatty acids, increased gluconeogenesis,
and decreased insulin clearance by the liver. Alternatively, in
a multisite study in adults, insulin resistance as well as fat mass
and distribution were independently associated with metabolic
risk (73). There has been an increase in the prevalence of metabolic
syndrome (74), with increases in hypertension, waist
circumference, and hypertriglyceridemia, which account for
much of the increased prevalence compared with fasting hyperglycemia
and low HDL concentrations (75).
Cook et al (69) noted that the prevalence of metabolic syndrome
using the third National Health and Nutrition Examination
Survey (NHANES III) data set was 28.7% among adolescents
with BMIs .95th percentile. This contrasts to a prevalence of
31.2% using the de Ferranti criteria (70) in the same data set.
The prevalence of metabolic syndrome appears to be increasing,
with 4.2% prevalence overall in the NHANES III, rising to 6.4%
in the NHANES 1999–2000 data (76), and, most recently to
8.6% (77). Earlier studies noted a similar temporal trend in
obesity, which suggests that longitudinal changes in the variables
associated with metabolic syndrome are due, in part, to the
rising prevalence and severity of obesity (78) and that childhood
overweight and obesity are most strongly associated with adult
clustering of variables associated with the metabolic syndrome
(72). The prevalence of metabolic syndrome in adolescents increases
with higher BMIs; the odds of metabolic syndrome were
1.55 greater for every half-unit increase in BMI z score (79). The
prevalence of metabolic syndrome appears to be greater in male
than in female adolescents and in Hispanics and whites when
contrasted to blacks (77).
Several studies note the increased risk of several cancers with
obesity. An increase of BMI by 5 was associated in men with an
increased risk of esophageal adenocarcinoma [relative risk (RR):
1.52], as well as thyroid (RR: 1.33), colon (RR: 1.24), and renal
(RR: 1.24) cancers, and, in women, of endometrial (RR: 1.59),
gallbladder (RR: 1.59), and esophageal (RR: 1.51) adenocarcinomas,
and renal (RR: 1.34) cancer. There was a reduced risk of
premenopausal breast cancer with obesity but an increased risk of
postmenopausal breast cancer (80). Therefore, the links between
childhood and adolescent obesity and adult diseases, specifically
cancer and cardiovascular diseases, are noted within this article.
A recent review examining the potential links between obesity
and cardiovascular disease included fetal origins, epigenetic
regulation, metabolic programming, and inflammatory changes
whereas other authors have suggested fat patterning, with increased
central adiposity, as a link (81).
The “thrifty gene hypothesis,” as proposed by Hales and Barker
(82), suggests that malnutrition during fetal and early postnatal
life leads to modifications in physiologic functions to improve
early survival. The thrifty gene hypothesis should not be confused
with the “catch-up growth” hypothesis as described by Cianfarani
et al (83) regarding the effects of poor fetal growth on obesity and
comorbidity risk. These physiologic and metabolic changes may
predispose to later disease, consistent with a longitudinal study
that showed that those with coronary artery disease, as well as type
2 diabetes, grew slowly in infancy and fetal life, but increased
their BMI rapidly during childhood (84). Epigenetic regulation
(changes in gene expression through DNA methylation or histone
CHILDHOOD OBESITY AND ADULT MORBIDITIES 1501S
modification) (85) may affect pre- and postnatal growth patterns
and mediate metabolic programming. These links between obesity
and cardiovascular disease and type 2 diabetes can be extended
to obesity and cancer. For example, several studies
describe associations between obesity and breast cancer and the
potential contribution of insulin resistance and adipokines (86,
87). There is increasing recognition that fat tissue is a regulator of
inflammation (88) and that enlarged adipocytes promote inflammation
(89). At a molecular level, leptin and proinflammatory
cytokines lead to the induction of aromatase activity, and subsequently,
to the production of estrogen (90, 91) as well as insulin
resistance. Alternatively, adiponectin resistance in transgenic/
knockout mice (genetic models of resistance to insulin’s indirect
effects on hepatic gluconeogenesis) was shown to exacerbate
insulin resistance (92), which implies that adiponectin is a cause
rather than a result of insulin resistance. Adiponectin expression is
down-regulated by greater insulin concentrations, and several
studies have noted an inverse relation between adiponectin
concentrations and breast cancer risk (93–96).
Obesity is associated with lower serum vitamin D concentrations;
however, it is possible that obese individuals simply store
more of this fat-soluble vitamin in a bioinactive form as a result of
their adiposity. Low serum vitamin D concentrations were observed
in 74% of obese adolescents and 32% of controls. In this
study, vitamin D status was influenced by dietary intake of vitamin
D, season, race and ethnicity, and degree of adiposity (97).
Measures of adiposity, such as BMI and waist circumference,
were modestly associated with vitamin D (98). The relation
between obesity and vitamin D appears to be related to both
dietary factors and decreased subcutaneous conversion (99). The
relation between obesity and cancer may also bemediated through
vitamin D. Vitamin D deficiency is noted as relating to cancer as
well as to other disorders (100, 101). Finally, circulating concentrations
of vitamin D have shown an inverse correlation with
insulin sensitivity, the incidence of type 2 diabetes, body fatness,
and other phenotypes associated with themetabolic syndrome (eg,
dyslipidemia) in adults and adolescents (97, 102, 103).
Two factors related to obesity, dietary intake and physical
activity, may also affect the risk of cancer. In a review of prospective
studies, the only dietary factors strongly associated with
cancer were alcohol consumption, obesity, and weight gain (104).
In the European Prospective Investigation into Cancer and Nutrition
(EPIC) study, there was a decreased incidence of cancers
among vegetarians when contrasted to meat eaters (105). Several
studies have examined the relation between cancer and physical
activity, with many examining the relation between breast cancer
and physical activity. Lifetime physical activity was associated
with decreased risk of breast cancer; in one study, recreational
activity, especially in late adolescence and early adulthood, was
protective (106). Other studies also documented the relation
between recreational activity and breast cancer (107, 108). One
additional study noted that forms of physical activity such as
household or occupational activities reduced risk, but recreational
activities did not affect the risk of developing breast cancer
(109).

It is well known that obesity, glucose intolerance, hypertension, and hypercholesterolemia in

adulthood increase mortality rates. We conducted the present study to determine whether the
presence of these risk factors in childhood predicts premature death. The rate of death from
endogenous causes in the highest quartile of childhood BMI was more than double that in the
lowest quartile, and the rate in the highest quartile of childhood two-hour plasma glucose levels
during a 75-g oral glucose-tolerance test was 73% higher than that in the lowest quartile.
Although neither blood pressure nor cholesterol level in childhood, when included as a
continuous variable, significantly predicted premature death, childhood hypertension increased
the risk of premature death from endogenous causes by 57%.
The absence of an association between premature death and cholesterol levels may be due
partly to the low proportion of deaths due to cardiovascular disease in this cohort (13.3%).
Treatment for any of the predictor traits during childhood or during adulthood did not appear
to explain the pattern of association (data not shown). No childhood risk factor that was
examined significantly predicted rates of premature death from external causes.
Childhood obesity predicted premature death from endogenous, but not external, causes. The
study was not powered to analyze effects on more specific categories of cause of death.
Including only liver-related causes of death in the analysis reduced the magnitude of the
association of premature death with childhood BMI and with the 2-hour glucose level, but the
direction and pattern of associations were similar to those observed when all endogenous causes
of death were included.
We considered whether the relationship between childhood BMI and premature death reflects
associations with adiposity or some other component of body mass. Our study began before
the availability of modern adiposity measures such as dual-energy x-ray absorptiometry.
However, we previously reported relationships between BMI and adipose mass and between
adipose mass and the cardiovascular risk factors in this population19; in that study, BMI and
adiposity were strongly correlated (r>0.96), varying little with age and sex, and BMI and
adipose mass were similarly correlated with the cardiovascular risk factors. Thus, the
observations for childhood BMI reported here are likely to reflect a positive association
between adiposity and rates of premature death.
In a study involving 508 U.S. adolescents (13 to 18 years of age) who were born between 1922
and 1935, overweight (>75th percentile of the sample distribution) was associated with
increased rates of death due to coronary heart disease.20 Two studies have assessed the
relationship between body weight and mortality in European birth cohorts from the early 20th
century.21,22 In a study of 2299 Welsh children born between 1937 and 1939, there was no
association between childhood BMI and death from cardiovascular causes. 21 However, there
was an association between childhood BMI and death from all causes; the lowest rate of death
was seen in the next-to-lowest BMI quartile and the highest rate of death in the highest quartile,
suggesting that, as in the case of adult Pima Indians,23 a U-shaped relationship exists between
obesity and mortality. In the second European study, involving 504 overweight children and
adolescents admitted to hospitals in Stockholm between 1921 and 1947, weight gain between
puberty and young adulthood was associated with cardiovascular disease, diabetes, and death
from all causes.22 A limitation of these studies is that obesity was uncommon during the study
period. For example, of the 2299 children in the Welsh study,21 only 92 (4.0%) had a BMI
above the 90th percentile for the age-specific and sex-specific distributions of the 1990 British
population, and British children in 1990 were leaner than their contemporary counterparts. 24
In the Arizona Pima Indians, unlike most other ethnic groups, childhood obesity has been
common for decades.25 It has been estimated that at the turn of the 21st century, approximately
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15% of U.S. children between the ages of 6 and 19 years (11 million children) were overweight
or obese,26 a prevalence that is unlikely to decline in the near future27 and that is triple the
prevalence among children of the same age in the 1960s.28,29 In the present study, 1394 children
(28.7%) were obese (BMI, ≥95th percentile on the 2000 CDC growth charts). This prevalence
is similar to that observed in contemporary Hispanic and African-American children.27 Thus,
although we studied a population with high rates of obesity and diabetes, our findings may
reflect the future burden of premature death among contemporary children from other ethnic
groups and may be more generalizable than the findings in previous studies.
In this study, we compared mortality rates with several clinical risk factors as variables.
Adjusting the obesity models for the development of diabetes in adulthood did not significantly
alter the risk estimates, whereas adjusting the glucose models for subsequent diabetes did
attenuate the association between childhood glucose levels and premature death. Hence,
dysregulated glucose metabolism in childhood may be a mediator of the effects of childhood
obesity on mortality rates, but it does not appear to be the sole or dominant factor; however,
the association between childhood glucose intolerance and premature death does appear to be
mediated by the development of subsequent diabetes.
The pattern of the relationships between the risk factors and observed mortality supports the
view that childhood obesity is an early metabolic derangement, whereas most of the other risk
factors evolve later. In fact, the predictive power of a risk score for type 2 diabetes (including
measures of obesity and insulin, blood-pressure, glucose, and lipid levels) in children is almost
entirely dependent on abdominal obesity, whereas in adolescents, the risk profile has evolved
to include obesity, hyperglycemia, and dyslipidemia.30 Our findings complement those in our
previous study, which showed that type 2 diabetes, when it occurs during adolescence in this
population, strongly predicts subsequent renal failure and death.2
Although there was no significant association between childhood hypercholesterolemia and
death before 55 years of age in this young cohort, an elevated cholesterol level in childhood
may emerge as a significant risk factor and other causes of death may predominate if the cohort
is followed to older ages. Cholesterol levels, however, are lower in American Indians than they
are in most other ethnic groups,31 a finding that may partially explain the absence of association
for this trait. The relationship between BMI and high-density lipoprotein (HDL) cholesterol is
relatively strong in Pima children (r = −0.3 to −0.6), but the relationship between BMI and
total cholesterol is weaker (r = 0.1).19 The effect of BMI on premature death might be
attributable in part to low HDL-cholesterol concentrations, which were not measured in most
of the study participants. Nevertheless, we speculate that low HDL-cholesterol levels are likely
to mediate rather than confound this relationship.
It is possible that the relationship between childhood BMI and mortality is confounded by
unmeasured lifestyle factors. Nevertheless, obesity can be both the cause and the consequence
of adverse lifestyle factors such as physical inactivity, excessive caloric intake, and specific
nutrient preferences. Thus, such factors may be important components of the causal pathway
between obesity and death. It is also possible that genetic factors have pleiotropic effects on
BMI and mortality.
Childhood obesity is predictive of excess mortality in several divergent settings,20-22 indicating
that obesity itself is causally related to either death or other commonly related factors. Even if
preventing childhood obesity does not affect the risk of death, increased physical activity and
modification of diet are likely to have long-term benefits. The lack of specific data on such
factors is a limitation of this study.
In summary, obesity in children who do not have diabetes is associated with an increased rate
of death from endogenous causes during early adulthood, an association that may be partially
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mediated by the development of glucose intolerance and hypertension in childhood. In contrast,
the cholesterol level in childhood is not a major determinant of premature death in this
population. Childhood obesity is becoming increasingly prevalent around the globe. Our
observations, combined with those of other investigators, suggest that failure to reverse this
trend may have wide-reaching consequences for the quality of life and longevity. Such evidence
underscores the importance of preventing obesity starting in the early years of life.

Results
Caloric intake, body and fat pad weights, and serum
leptin
There were no differences in caloric intake among the groups:
Obesity-Prone, 9,481 ± 193 (n = 18); Obesity-Resistant,
8,647 ± 216 (n = 11); and Low-Fat, 9,157 ± 387 (n = 19)
(values are mean ± SEM, ANOVA p = 0.219, calculated for
mice that lived to the termination of the study). Obesity-Prone
mice were 45% heavier than either Obesity-Resistant or Low-
Fat mice at the termination of the experiment (p < 0.001)
(Table 1). Additionally, combined retroperitoneal and parametrial
fat pad weights of Obesity-Prone mice were 4.5 and 9
times heavier than those of Obesity-Resistant and Low-Fat
mice, respectively (Table 1). Interestingly, fat pads from Obesity-
Resistant mice were twice as heavy as those of Low-Fat
mice despite the similar body weights of these two groups.
However, the fat pad weights for Obesity-Resistant and Low-
Fat mice were not significantly different by the Newman-Keuls
test following ANOVA, when these values were analyzed by
Student t test (p = 0.0174). Serum leptin levels were significantly
higher in Obesity-Prone mice compared with Obesity-
Resistant (p < 0.01) and Low-Fat (p < 0.001) mice (Table 1).
Similar to fat pad weights, Obesity-Resistant mice had serum
leptin levels that were twice those of Low-Fat diet mice; again,
this difference was not significant using the Newman-Keuls
test following ANOVA but was significantly different when
compared by the Student t test (p < 0.03). When data from all
mice were pooled, there was a significantly (p < 0.0001) positive
correlation of fat pad and body weights to serum leptin
levels (Figure 1a,b). Similar results were obtained for individual
groups (data not shown).
Mammary tumor development
Obesity-Prone mice had an overall MT incidence of 79% compared
with 71% for Obesity-Resistant mice and 55% for Low-
Fat mice (Table 2). Overall MT incidence is defined as (a) all
MTs classified as adenocarcinomas and initially detected by
palpation and (b) those nonpalpable MTs discovered at
necropsy. These values were not significantly different from
each other, although chi-square analysis between Obesity-
Prone and Low-Fat mice had a p value of 0.07. When incidence
rates for palpable MTs were determined, values were
55%, 29%, and 10% for Obesity-Prone, Obesity-Resistant,
and Low-Fat mice, respectively. These results were significantly
different for comparisons among the groups (p =
0.0038) with specific differences between Obesity-Prone and
Obesity-Resistant (p = 0.09), Obesity-Prone and Low-Fat (p =
0.0012), and Obesity-Resistant and Low-Fat (p = 0.21) (Table
2).
There was a significant difference among the groups with
respect to age of palpable MT detection (Table 2). There was
also a significant difference between the Low-Fat and Obesity-
Prone groups of almost 8 weeks. The latency for overall MT
development is not shown as the results are affected by the
fact that most of the MTs in the Low-Fat and Obesity-Resistant
groups were found at 85 weeks of age, when the mice were
euthanized because this was the termination point of the
study.
Average MT weights per tumor-bearing mouse were 2.41,
1.30, and 0.65 g for Obesity-Prone, Obesity-Resistant, and
Low-Fat mice (p = 0.0016), respectively (Table 2). Although
the average MT weight for Obesity-Resistant mice was twice
that of Low-Fat mice, this did not reach statistical significance.
There was a trend toward increased MT number per tumorbearing
mouse for mice fed the high-fat diet regardless of
body weight classification; however, this did not reach statistical
significance either. Interestingly, six Obesity-Prone mice
had MTs classified as high-grade adenocarcinoma compared
with none for the other two groups.
Leptin signaling protein and mRNA expression in
mammary tumor and mammary fat pad
Because there were no significant differences between Obesity-
Prone and Obesity-Resistant mice, protein expression levels
for these two groups were combined and termed High-Fat.
Protein expression levels of ObRb, Jak2, and pSTAT3 were
significantly lower in MT samples from High-Fat mice compared
with those from Low-Fat mice (p < 0.05) (Figure 2a). On
the other hand, leptin and ObR protein expression levels were
similar between the two groups. In addition, MTs obtained
from Low-Fat mice had significantly higher mRNA expression
levels of leptin, ObR, ObRb, and STAT3 (p < 0.01) than those
of High-Fat mice (Figure 2b).
Table 1

Obesity
Excess body weight has been estimated to account for over 40% of renal cell cancers in the
United States and over 30% in Europe.23 In prospective studies conducted worldwide,
overweight and obese individuals at baseline were found to have elevated subsequent risks
of renal cell cancer in a dose-response manner,24-27 estimated to increase 24% for men and
34% for women for every 5 kg/m2 increase in body mass index (BMI).28 Waist-to-hip ratios,
weight cycling, and weight gain during adulthood also have been implicated, but their
impacts are difficult to disentangle from effects of BMI per se.12 The prevalence of obesity
has increased markedly not only in high-resource countries such as the United States and
Western Europe, but also in low- and middle income countries since the 1980s.29 The global
rise in obesity likely has contributed to the upward RCC incidence trends, but does not
explain the recent leveling of RCC in some countries. Several mechanisms have been
hypothesized to influence renal cell cancer development in obese individuals, but direct
evidence in humans is limited. These include chronic tissue hypoxia, insulin resistance and a
compensatory hyperinsulinemia, altered endocrine milieu and production of adipokines,
obesity-induced inflammatory response, and lipid peroxidation and oxidative stress.30

Obesity, the most common nutritional disorder in industrialized

countries, is associated with an increased mortality
and morbidity of cardiovascular disease (CVD) [1]. The
World Health Organization estimates that more than 1
billion adults worldwide are overweight, 300 million of
whom are clinically obese—defined as having a body mass
index (BMI) equal to or greater than 30 kgm−2, or a
waist circumference greater than 94 cm for men and 80 cm
for women [2]. Obesity is a chronic, multifactorial, and
complex disease resulting from a long-term positive energy
balance, in which both genetic and environmental factors are
involved [3, 4]. It was recently suggested that some forms of
obesity are associated with chronic low-grade inflammation
[5].
CVDs, including heart disease, vascular disease and
atherosclerosis, are the most critical global health threat,
contributing to more than one-third of the global morbidity.
In most cases, these clinical conditions result from
atherosclerosis, which was once identified as a lipid-storage
disease. At the present time, CVD is recognized as a chronic
inflammatory condition of the vessel wall that results from
the transendothelial passage (transcytosis) of cholesterolrich
atherogenic Apo-B lipoproteins (VLDL, IDL and LDL)
from the plasma into the intima. These lipoproteins are
retained in the subendothelial space, which leads to infiltration
of macrophages and T cells that ultimately then
interact with each other and with the cells of the arterial
wall [6, 7]. It is likely that inflammation induced by obesity
accelerates the atherosclerosis. Adipose tissue is recognized
as an important player in obesity-mediated CVD. In 1994,
adipose tissue was first identified as the source of the
hormone leptin, opening the door for a new era of research
that focused on adipocyte endocrinology [8]. It is now
apparent that adipocytes have a more complex physiological
role [9]. Adipocytes produce large numbers of hormones,
peptides, and other molecules that affect cardiovascular
function, not only in an endocrine manner, but also by
autocrine and paracrine mechanisms [10]. This might lead
to cytokine-mediated inflammatory, changes in the liver,
systemic inflammation and atherosclerosis.

Systemic Inflammation. As individuals become obese

and their adipocytes enlarge, the adipose tissue undergoes
molecular and cellular alterations that subsequently affect
systemic metabolism (Figure 2). First, macrophages accumulate
within adipose tissue, leading to local inflammation. Several
proinflammatory factors are produced in adipose tissue
as obesity increases. When compared to lean individuals,
adipose tissue in obese individuals shows higher expression
of proinflammatory proteins, including TNF-α and IL-
6 [21, 22]. Macrophage numbers in adipose tissue also
increase with obesity [23], apparently acting as scavengers
4 Mediators of Inflammation
IL-1β
IL-1R1 IL-1RAcP
IL-6 IL-1Ra
NF-κB
MyD88
COX-2 iNOS
AA PGH2
PGE2
PGES
EP1 EP2 EP3 EP4
Regulation of CRP
Increase of fibrinogen
Endothelial dysfunction
CNS-food intake and energy balance
Regulation of leptin
CNS-food intake and energy balance
Modulation of sleeping
Figure 3: Interleukin-1β (IL-1β) induction of interleukin-6 (IL-6) and prostaglandin E2 (PGE2) signaling. IL-1β binds to the IL-
1R1/IL-
1R1AcP heterodimer, which then initiates the signaling cascade that causes the translocation of the transcription factor nuclear
factor-κB
(NF-κB) into the nucleus, where it induces the transcription of pro- and anti-inflammatory genes including inducible nitric oxide
synthetase
(iNOS), IL-6, IL-1Ra and cyclooxygenase-2 (COX-2). COX-2 catalyses the conversion of arachidonic acid (AA) to
prostaglandin H2 (PGH2).
PGH2 is converted into PGE2 by terminal PGE synthase (PGES). PGE2 signals occur via four different G-protein coupled
receptors, EP1REP4R,
each of which has multiple splice variants with different signaling properties.
of apoptotic adipocytes. It also has been reported that there
is a marked increase in these scavengers in obese subjects
[24]. Macrophage accumulation and the subsequent local
inflammation are believed to result in numerous metabolic
dysfunctions that accompany obesity, including systemic
inflammation and atherosclerosis.
Visceral fat secretes more cytokines than subcutaneous
adipose tissue [16]. A recent study elegantly demonstrated
that transplantation of visceral adipose tissue from genetically
obese mice into Apoe-deficient mice increased atherosclerosis
in the recipient animals, suggesting that inflamed
adipose tissue exerts distinct vascular effects, presumably
through inflammatory cells such as macrophages within the
visceral adipose tissue [25]. Macrophages within visceral
adipose tissue are known to express and release cytokines.
These cytokines reach the liver though the portal circulation,
where they can stimulate hepatic inflammation [26], thereby
inducing a chronic systemic inflammatory response.
4.2. Endothelial Dysfunction. Clinical and experimental data
support a link between systemic inflammation and endothelial
dysfunction. Mounting evidence shows that disturbed
endothelial function may be an early marker of an ongoing
atherosclerotic process. Thus, endothelial dysfunction has
increasingly been recognized to play an important role in a
number of conditions associated with a high prevalence of
atherosclerotic CVD. Inflammatory cytokines are important
protagonists in the formation of atherosclerotic plaques,
eliciting effects throughout the atherosclerotic vessel. Importantly,
the development of atherosclerotic lesions, regardless
of risk factors (e.g., diabetes, hypertension, obesity), is
characterized by the disruption of the normal function of
endothelial cells.
The reasons for coronary endothelial dysfunction are
complex and may involve ischemia/reperfusion injury.
Smoking, obesity, hypertension, diabetes, physical inactivity,
and hypercholesterolemia are established atherogenic risk
factors. Endothelial dysfunction is regarded as an early
stage of atherosclerosis, which is a chronic inflammatory
disease [27]. Chronic inflammation is a major contributing
factor to atherosclerosis and various markers of inflammation,
fibrinolysis, and coagulation are upregulated in
patients with established atherosclerotic disease. For vascular
homeostasis, endothelial cells are of the utmost importance
and they produce a variety of mediators, surface proteins,
and autacoids involved in vasomotion, coagulation, and
inflammation. Adipose tissue expresses enzymes involved in
the angiotensin system(RAS) (renin, angiotensin-converting
enzyme (ACE)), as well as the nonrenin-angiotensin system
(NRAS) (cathepsin D, cathepsin G, tonin, chymase) [28].
The identification of elevated CRP as a transient independent
risk factor for endothelial dysfunction might provide an
important clue for linking a systemic marker of inflammation
to the progression of atherosclerotic disease. Thus,
CRP has been proposed for risk assessment of CVD in
the at-risk general population. Available evidence suggests
that low-grade inflammation is accompanied by decreased
Mediators of Inflammation 5
bioavailability of endogenous NO and that TNF-α may play
a key role in these events. The adipose tissue constitutes
a source of other vasoactive factors, such as leptin, serum
amyloid A (SAA), or apelin, among others [29]. Since
blood vessels express receptors for most of the adipocytederived
factors, adipose tissue seems to play a key role in
cardiovascular physiology via the existence of a network of
local and systemic signals. Therefore, these data demonstrate
that markers of inflammation have independent predictive
value for clinical and subclinical CVD beyond that of the
traditional risk factors.
4.3. Subclinical Atherosclerosis and CVD. The development
of atherosclerosis in obesity stems from a constellation of
interrelated proatherogenic mechanisms. It is well established
that a higher BMI is associated with subclinical
inflammation, as reflected by increased CRP levels [30],
and increased systemic oxidative stress that is independent
of blood glucose and diabetes [31]. Recent evidence
has suggested that leptin stimulates cholesterol uptake by
macrophages, particularly in the presence of high glucose.
This then triggers the formation of foam cells and
the development of atheromatic lesions. Obesity-related
hypoadiponectinemia might also contribute to impaired
endothelial function, increased vascular ROS production and
overall proatherogenic effects [32]. Finally, increased release
of proinflammatory cytokines by adipose tissues, including
IL-6, IL-1, and TNF-α, sustains vascular wall inflammation
and promotes pro-atherogenic gene expression [33].
There is interest in identifying markers of subclinical
atherosclerosis, such as coronary artery calcium (CAC) and
carotid intimal medial thickness (CIMT), in order to facilitate
an earlier diagnosis and possible prevention of CVD.
CRP levels were found to be correlated with CIMT in a group
of young subjects [34], but not in older individuals [35]. In
other studies, levels of IL-6 have been shown to be associated
with the amount of CAC [36], and the CD40 ligand, which
is a marker of enhanced innate immunity, has been found
to be correlated with CIMT in human subjects [37]. Since
leptin levels have been shown to be associated with CAC
independently of body weight measures or other risk factors,
this points to a possible proatherogenic role for leptin [38].
5. Adipose Tissue-Derived Cytokines
Known to Affect Inflammation
5.1. CRP. Of the many positive and negative acute-phase
reactants, perhaps the most recognized is CRP, which is a
member of the pentraxin family that attaches to the plasma
membrane of damaged cells causing cell death through
activation of the complement cascade [39]. More than 20
prospective epidemiologic studies have demonstrated that
high-sensitivity CRP is an independent predictor of myocardial
infarction, stroke, peripheral arterial disease, and sudden
cardiac death, even in apparently healthy individuals [40, 41].
Clearly, CRP is one of the strongest markers of chronic
inflammation, and it has been reported that it also directly
participates in the coronary and aortic atherosclerosis that
leads to cardiac events [42].
Ouchi et al. [43] confirmed CRP mRNA expression
in human adipose tissue using quantitative real-time polymerase
chain reaction. In the same article, the authors
proposed that adipose tissue is an important source of
circulating CRP. However, they made no attempt to investigate
the stimuli able to induce CRP. Esposito et al.
[44] investigated the effects of weight loss and lifestyle
changes on vascular inflammatory markers in obese women.
After 2 years, they found that BMI, as well as the serum
concentrations of IL-6, IL-18, and CRP, decreased more in
the intervention group than in the control subjects, whereas
the adiponectin levels significantly increased. The beneficial
effects of a Mediterranean-style diet on endothelial function
and vascular inflammatory markers have been documented
in patients with metabolic syndrome. When compared
to patients consuming a control diet, patients consuming
a Mediterranean-style diet have significantly lower serum
concentrations of high-sensitivity CRP, IL-6, IL-7, and IL-18
as well as a decreased insulin resistance [45]. In a quartile
analysis of the percent weight reduction, the largest weight
reduction quartile did not show significant decreases in the
CRP levels, whereas the middle quartiles showed remarkable
CRP decreases. Based on inflammatory status, there may
be an optimal pace of exercise combined with weight loss
[46]. Two recent studies have demonstrated that exercise
training in conjunction with weight reduction significantly
affected the CRP levels, body composition, and human left
ventricular growth [47, 48].
5.2. Serum Amyloid A (SAA). Serum amyloid A (SAA), an
important marker of inflammation, is an apolipoprotein
that is mainly synthesized in mammalian liver [49]. Human
SAA is a 12.5-kDa protein whose levels can increase up to
1,000- fold in the serum 24–36 h after infection or injury,
decline after 4–5 days, and then return to baseline after
10–14 days [50]. The human genome encompasses four SAA
genes, of which three encode functional proteins. SAA1 and
SAA2 are highly homologous reactants whose concentration
can increase upon infection, trauma, and obesity [51, 52],
whereas SAA3 is a pseudogene and SAA4 is a constitutively
expressed minor constituent of the nonacute-phase HDL
[53].
SAA has proven to be a suitable and sensitive indicator of
the various stages of inflammation involved in inflammatory
disorders. SAA is comparable to CRP, as both are major
acute phase proteins that can increase up to 1,000-fold and
reach 1 mg/mL in the serum under stimulation [50]. They
can be produced by the liver under inflammatory stimuli,
and their effects are mediated through pro-inflammatory
cytokines (IL-1 and TNF-α) and “messenger” cytokines (IL-
6) [54]. However, in contrast to CRP, which is mainly
expressed in the human liver, SAA is expressed in both the
liver and adipose tissue. SAA is now accepted as an adipokine
that is produced by adipocytes and which directly mediates
obesity-associated inflammation. Hence, SAA might serve as
a better indicator of obesity and obesity-associated diseases,
6 Mediators of Inflammation
especially when vascular diseases and metabolic disorders are
present.
SAA is known to be amarker for obesity, as its expression
is well correlated with obesity [55]. Some studies have
shown that SAA levels are positively associated with BMI
levels and that weight loss led to decreased SAA levels. In
1999, Danesh et al. [56] first reported that concentrations
of SAA protein were strongly correlated with obesity. Since
then, more than ten studies have shown that SAA is
strongly associated with obesity [57–59]. In addition, it
has been shown that SAA gene expression is increased in
the adipose tissue of obese subjects and is significantly
correlated with adipocyte size and inflammatory biomarkers
[52].
Recent studies have shown that SAA elevation can
predict cardiovascular events analogously with or even better
than CRP by itself [60–62] and in this sense, it has been
speculated that SAA might be one of the links or even a
proatherogenic risk factor between inflammation and CVD
[63, 64]. SAA is able to both alter vascular proteoglycans in
a proatherogenic manner [65] and stimulate the production
of various inflammatory mediators in cultured vascular
endothelial cells, neutrophils, and monocytes [66]. Endothelial
cells, smooth muscle cells, monocytes, and macrophages
in atherosclerotic lesions have been reported to account
for the extrahepatic production of SAA, as the presence of
both SAA mRNA and protein products have been detected
in these cell types [67]. SAA has also been accepted as
being a biomarker of cerebrovascular disease and carotid
artery intima-media thickness, which is an early index
of atherosclerosis [68–71]. However, a very recent study
indicated that SAA does not mediate early atherosclerosis
[57].
SAA has also been found to be associated with metabolic
disorders, such as diabetes, insulin resistance, and metabolic
syndrome [72, 73]. Additionally, genes critical for insulin
sensitivity were also found to be downregulated in adipocytes
treated with recombinant SAA [74].
5.3. Leptin. Leptin, which was the first adipocyte hormone
identified, influences food intake through direct effects on
the hypothalamus [75]. The adipocyte-derived hormone
leptin has actions in the brain (e.g., hypothalamus, cortex
and limbic areas) and in a number of peripheral tissues as
well (e.g., cells of the pancreas, liver and immune system).
However, the central action of leptin in the brain, and in
particular the hypothalamus, has been best characterized
with regards to energy homeostasis and its importance
for reproductive functions [76]. Moreover, disruption of
peripheral leptin signaling in mice has been shown to cause
no significant changes in either the energy balance or glucose
homeostasis [77].
Mice lacking the gene coding for leptin (named ob/ob
mice) are obese and diabetic. When ob/ob mice are treated
with regular injections of leptin, they show reduced food
intake, increased metabolic rate, and weight loss [78].
These effects appear to be mediated mainly by the central
nervous system, as intracerebroventricular injection of leptin
produces significant effects at much lower doses than those
required by systemic injection. Systemic injections of leptin
have a beneficial effect in children with congenital leptin
deficiencies [79]. In a pioneering study, administration of
exogenous leptin to individuals with lipoatrophic diabetes
resulted in marked reductions in triacylglycerol concentrations,
liver volume, and glycated hemoglobin. Ultimately,
this treatment resulted in the discontinuation of or large
reductions in the patient’s antidiabetic therapy [80]. Unfortunately,
leptin concentrations are already high in most
obese individuals because of the increased amount of leptinsecreting
adipose tissue [81]. In these individuals, increasing
the leptin concentrations only induces the target cells to
become resistant to actions of the hormone. Therefore,
further studies need to be undertaken to clarify potential
therapeutic strategies using leptin in these types of patients.
Leptin is involved in the control of not only energy homeostasis
but also immunity. During fasting/starvation, when
plasma leptin levels decline, neural pathways in the hypothalamus
cause the appetite to increase and energy expenditure
to decrease as the body attempts to restore its fat stores
[82]. In addition, the fall in plasma leptin diminishes thyroid
hormone production and inhibits the reproductive axis, both
of which help to save energy during nutritionally lean times
[83]. These metabolic effects of leptin are in part centrally
mediated by activation of the hypothalamic-sympathetic
nervous system axis [84]. In addition to the complete leptin
deficiency disorder, relative leptin deficiency is an emerging
clinical syndrome that is now being seen more often in
several clinical conditions, including congential or acquired
lipodystrophy as well as exercise-induced energy deficiency
and hypothalamic amenorrhea or anorexia nervosa. Leptin
replacement therapy might prove to be a therapeutic option
for patients with these disorders [85]. Very recently, administration
of chemical chaperones that decrease ER stress also
restored leptin sensitivity in diet-induced obese mice [86].
In obese subjects who have lost weight, modifications that
lead to decreased energy expenditure may predispose the
individual to regain the weight. However, when subjects are
administered “replacement” doses of leptin that restore their
circulating leptin concentrations to preweight-loss levels,
the weight gain can be prevented [87]. This suggests that
the weight-reduced state is a condition of relative leptin
deficiency. Recent reports have shown that in addition
to its action on the hypothalamus, leptin may also act
on the cortex and limbic areas, which are involved in
cognitive and emotional regulation of feeding behavior [88].
Teleologically, the adaptations mediated by reduced leptin
may have evolved as a protection against the threat of starvation
by limiting energy use and enhancing energy storage
[89].
The potential effects of leptin in the pathophysiology of
cardiovascular complications of obesity remain diverse [90].
While some studies [91, 92] have indicated that circulating
leptin levels are not significantly related to the risk of CVD
or mortality in a diabetic population, these studies did find
that leptin was associated with obesity and inflammatory
markers. Even so, other reports have suggested that leptin
does contribute to atherosclerosis and CVD in obese subjects
Mediators of Inflammation 7
[93]. Therefore, this protein may elevate the blood pressure
by stimulating the autonomic nervous system. Leptin has
been found to have multiple effects on the cells of the artery
wall. In human vascular endothelial cells, leptin upregulates
the expression of the plasminogen activator inhibitor-1
[94], and leptin also helps modulate ACAT1 expression
and cholesterol efflux from human macrophages [95]. In
addition, leptin has been reported to increase nitric oxide
(NO) bioavailability in blood vessels via the activation of
endothelial NO synthase (eNOS) [96] and inducible NO
synthase (iNOS) [97] in the endothelial and smooth muscle
cells, respectively. Recent studies that measured coronary
artery disease have demonstrated that hyperleptinemia
was associated with coronary atherosclerosis [98, 99], with
the association determined to be independent of insulin
resistance. Other studies have shown that leptin may have a
role in neointimal formation in response to arterial injury
[100, 101]. In fact, very obese, leptin-deficient mice have
been found to be protected from atherosclerosis despite all
of the metabolic risk factors, suggesting that this hormone
may directly contribute to the risk of vascular disease [102].
Moreover, in a prospective study in humans in which
anthropometric and metabolic risk factors were controlled,
the circulating leptin concentrations were shown to be an
independent risk factor for predicting cardiovascular events
[103]. Therefore, when chronically elevated concentrations
of leptin are seen in obese individuals, this may indicate
a predisposition to progression of atherosclerosis in these
individuals.
5.4. Adiponectin. Adiponectin is a product of adipocytes, and
its levels in humans decrease in obese subjects [104]. As one
of the most extensively studied adipokines, adiponectin has 3
different oligomers, each of which may have a different biological
function [105]. The major receptors for adiponectin
are AdipoR1 and AdipoR2. These belong to a new family of
receptors that are predicted to contain seven transmembrane
domains but which will be structurally and functionally
distinct fromthe G-protein coupled receptors. A recent study
has shown that AdipoR2 stimulates energy dissipation by
increasing fatty acid oxidation while inhibiting oxidative
stress and inflammation [106, 107]. Adipocytes secrete high
levels of adiponectin that then exert anti-inflammatory
effects, most notably in atherosclerotic plaques [108]. These
effects occur due to the suppression of TNF-α and proinflammatory
cytokines such as IL-6 and interferon-c, along with
the induction of other anti-inflammatory factors such as
the IL-1 receptor antagonist [109]. In contrast, adiponectin
levels have been shown to be low in several different forms
of insulin resistance. In vivo, adiponectin enhances energy
consumption and fatty acid oxidation in the liver andmuscle,
which reduces the tissue triglyceride content, thereby further
enhancing the insulin sensitivity [110]. In adiponectin transgenic
mice, there is improvement of the lipid profile [111,
112], and when plasma triglycerides are reduced, this leads to
an increased VLDL catabolism in the skeletal muscle [113].
Taken together with its metabolic and anti-inflammatory
effects, it has been proposed that adiponectin not only
contributes to the beneficial effects of body weight loss but
also has a role in modulating the cardiovascular system.
As might be expected based on the above observations,
adiponectin promotes an antiatherogenic and antiinflammatory
program of gene expression and function in
the vessel wall. Adiponectin downregulates the expression
of adhesion molecules on the endothelial cells and directly
improves endothelial dysfunction [114, 115]. Adiponectin
also reduces proliferation in a receptor-independent fashion
in the vascular smooth muscle cells [116]. In a very recent
study, it has been shown that adiponectin reduces lipid
accumulation, down-regulates the expression of scavenger
receptors in macrophages, and promotes macrophage polarization,
all of which play a role in anti-inflammatory
activities [117]. Other studies have also indicated that
adiponectin has an important role in cardiovascular protection.
Hypoadiponectinemia is found in patients with angiographically
demonstrated coronary artery disease [118]. In
obese children, it has been reported that reduced adiponectin
concentrations are of more importance than conventional
cardiovascular risk factors, and that this inflammation status
is related to early atherosclerosis [119]. However, in a large
prospective study that was combined with a meta-analysis
of previously published prospective studies, the adiponectin
levels at baseline were found to be rather weak predictors
of CVD risk [120]. However, other studies have shown that
adiponectin exerts beneficial effects at nearly all stages of the
atherogenesis process [121], and that the adiponectin levels
are inversely correlated to the progression of the coronary
artery calcium in both diabetic and nondiabetic subjects
[122]. Serum total and high-molecular weight adiponectin
are also associated with biomarkers of inflammation, insulin
resistance, and endothelial function, all of which are independent
risk factors of CVD [123].
5.5. Resistin. Resistin, which is one of the most recently
identified adipokines, has been proposed to be an inflammatory
marker for atherosclerosis. While it has been shown
to induce increases in CRP production by the macrophages
[124], resistin is an example of the new adipokines that
appear to have contrasting roles when examined in mice versus
humans. For example, confirmation of the results found
in mice has proven to be difficult in human populations.
This may be due to the fact that resistin appears to be
derived from different sources in humans as compared to
rodents. This protein was initially shown to be released
in large amounts from mouse adipocytes, with obese mice
having elevated levels that were accompanied by insulin
resistance [125]. However, investigations in humans suggest
that resistin is expressed in adipocytes with monocytes and
macrophages [126, 127]. This lack of homology between
the human and mouse resistin genes suggests a potential
divergence in function [128]. Since macrophages are known
inflammatory modulators, resistin may be an inflammatory
marker in humans. Supporting this possible inflammatory
role in humans are results that show recombinant
resistin activates human endothelial cells, as measured by an
increased expression of endothelin-1 and various adhesion
8 Mediators of Inflammation
molecules and chemokines, while simultaneously increasing
the CD40-ligand signaling by down-regulating the tumor
necrosis factor receptor-associated factor-3 [129]. Moreover,
Calabro et al. [130] has shown that resistin can promote
human coronary artery smooth muscle cell proliferation by
activation of the extracellular signal-regulated kinase 1/2
(ERK) and phosphatidylinositol 3-kinase (PI3 K) pathways.
Taken together, these findings suggest a possible mechanistic
link between resistin and cardiovascular disease via proinflammatory
pathways.
In addition, there have been many recent reports that
support a role for resistin in obese rodent models. Resistin
has been found to modulate nutritional regulation and may
possibly play a role in maintaining fasting blood glucose
levels [131]. Further rodent studies have also suggested that
resistin mRNA levels are higher in abdominal fat depots,
as compared to deposits in the thigh [132], and that these
serum resistin levels are positively correlated with BMI
[133]. Recent investigations in humans have shown there are
higher serum resistin levels in obese subjects as compared
to lean subjects. These higher levels were also positively
correlated with changes in the BMI and the visceral fat
area [134, 135]. Lee et al. [136] found higher circulating
resistin levels in obese mice when compared to their lean
counterparts. Additional studies have reported significant
reductions in circulating resistin levels following moderate
weight loss [137] and postgastric bypass [138]. Collectively,
these observations suggest that resistin may indirectly be
involved in the nutritional regulation in humans.
5.6. Visfatin. Visfatin, also known as nicotinamide phosphoribosyltransferase
(NAMPT), which was previously known
as a pre-B cell colony-enhancing factor (PBEF), functions as
a growth factor for early B cells within the immune system
[139]. Fukuhara et al. [140] demonstrated that visfatin
is a secreted protein that is expressed and regulated by
the adipose tissue. As compared to subcutaneous adipose
tissue, there are greater amounts of visfatin within visceral
fat depots. Furthermore, this study indicated that visfatin
could bind to and activate insulin receptors, similar to that
seen for insulin both in vivo and in vitro. However, this
effect of visfatin is controversial. For example, Revollo et
al. were unable to reproduce the insulin-mimetic activity
of this protein, even though a significant physiological
role in the regulation of beta-cell function through the
NAD biosynthetic activity was detected. Thus, the authors
suggested that NAMPT could play an important role in
the control of glucose metabolism [141]. After these novel
findings, Fukuhara et al. decided to retract their previously
published paper [142].
The visfatin peptide was originally discovered in the liver,
skeletal muscle, and bone marrow and found to act as a
growth factor for B-lymphocyte precursors. This peptide is
not only produced by white adipose tissue (WAT), but also
by endotoxin-challenged neutrophils, and is able to prevent
apoptosis via a mechanism mediated by caspases 3 and 8
[143]. Circulating visfatin levels are closely correlated with
WAT accumulation and visfatin mRNA levels increase in the
course of adipocyte differentiation. Visfatin expression is upregulated
by IL-6 and TNF-α, and is down-regulated by GH
[144]. Insulin has no effect on visfatin mRNA [145]. Moreover,
visfatin is up-regulated by the peroxisomal proliferatoractivated
receptor (PPAR)-alpha and PPAR-gamma agonists
in obese rats. Since it has been shown to be associated with
improved glycemic control and lipid profiles, this suggests
that PPAR-alpha and PPAR-gamma agonists may act, at least
in part, via the up-regulation of visfatin expression [146].
In addition to inducing chemotaxis and the production of
IL-1, TNF-α, IL-6, and costimulatory molecules by CD14C
monocytes, visfatin also increases their ability to induce
alloproliferative responses in lymphocytes, effects which are
mediated intracellularly by p38 and MEK1 [144].
Possible associations between circulating visfatin and
anthropometric or metabolic parameters in obesity and type
2 diabetes have been found in some but not all reported
studies [147–149]. These contradictory findings may be
due in part to the considerable differences found in the
visfatin immunoassays [150]. In human studies, it has been
shown there is a positive correlation between the visceral
adipose tissue visfatin gene expression and BMI, along with
a negative correlation between BMI and subcutaneous fat
visfatin [151]. This suggests that visfatin regulation varies
within different depots and that the adipose depot ratios
are highly dependent upon the obesity of the subjects. A
wide population study in humans has recently discovered
a direct correlation between plasma visfatin and the BMI
and body fat content in males only. This study failed to find
any differences in the expression between the visceral and
subcutaneous fat depots [152].
Several studies have shown that there are different disorders
that exhibit altered plasma levels of this protein [153–
156]. Thus, visfatin plasma concentrations may potentially
be related to lipid metabolism [157] and the inflammatory
response [158]. Since an increased expression of this protein
has been observed in the macrophages of unstable carotid
and coronary atherosclerosis in humans [159], and there is
a negative association between the visfatin plasma levels of
visfatin and vascular endothelial function [160], it has been
proposed that visfatin plays a role in plaque destabilization.
NAMPT, which was originally identified as PBEF, has been
shown to act as a cytokine independent of its enzymatic
activity, and thus plays a major part in regulating immune
responses [161]. Since NAMPT has been implicated in
the pathogenesis of several acute or chronic inflammatory
conditions, such as atherosclerosis and CVD [161], it may
act as a pro-inflammatory cytokine and potentially have a
beneficial effect on insulin secretion.
At the present time, the role of visfatin in the modulation
of glucose metabolism, as well as its ability to bind to the
insulin receptor is still under debate [162–164]. As a number
of inconsistencies among the different visfatin studies exist,
the role of this adipokine in obesity and insulin resistance
has yet to be clearly defined.
5.7. Chemerin. Recently, chemerin (retinoic acid receptor
responder 2, tazarotene-induced gene 2) was found to be
Mediators of Inflammation 9
highly expressed in adipose tissue and liver [165]. Chemerin
is an agonist of the orphan G-protein coupled receptor
chemokine-like receptor 1 (CMKLR1, ChemR23) [166] that
is expressed by cells of the innate immune system [167].
Therefore, chemerin might be further evidence of a link
between obesity and inflammation. Chemerin is secreted as
an inactive precursor, and then activated through proteolytic
cleavage by serine proteases of the coagulation, fibrinolytic
and inflammatory cascades. Chemerin appears to be a novel
and promising adipokine, and in several recent studies,
human chemerin plasma levels have been shown to have
a significant association with the BMI, inflammation, and
metabolic syndrome [168–170].
Platelets have been found to be a rich cellular source
of chemerin. In some pathological conditions, chemerin is
activated and then released, which leads to the elevation
of blood chemerin levels [171]. Recent studies have shown
that both adipocytes [172] and fibroblast cells [173] can
produce chemerin. Chemerin has also been measured in
a number of human inflammatory exudates, including
ascitic fluids from human ovary cancer and liver cancer,
as well as synovial fluids from arthritic patients [174].
Angiotensin-converting enzyme (ACE) may be responsible
for the activation of prochemerin. If so, as has been shown
in vitro, this effect should be able to be blocked by an ACE
inhibitor such as captopril [175]. However, further studies
will be necessary to clarify this potential mechanism in
vivo. There is also growing evidence that the bioactivity of
chemerin is closely regulated by proteolytic cleavage in the Cterminal
region, which may control its maximal chemotactic
or anti-inflammatory effects [176].While the primary amino
acid sequences indicate that chemerin is structurally distinct
from the CXC and CC chemokines, it functions exactly
like a chemokine and can induce leukocyte migration and
intracellular calcium mobilization. Chemerin also exerts
potent anti-inflammatory effects on activated macrophages,
which express the chemerin receptor CMKLR1 (chemokinelike
receptor-1) in a cysteine protease-dependent manner
[177].
Chemerin is a newly described adipokine with effects
on adipocyte differentiation and metabolism in vitro [165].
In rodents, there is conflicting data with regard to the
association of chemerin with obesity and diabetes. While
there is a decreased chemerin expression in the adipose tissue
of db/db mice as compared with controls [178], chemerin
expression is significantly higher in the adipose tissue of
impaired glucose tolerant and diabetic Psammomys obesus
as compared with normal glucose-tolerant sand rats [179].
It has also been demonstrated that chemerin or chemerin
receptor knockdown impairs the differentiation of 3T3-L1
cells into adipocytes, reduces the expression of adipocyte
genes involved in glucose and lipid homeostasis, including
adiponectin and leptin, and alters the metabolic functions
in mature adipocytes [170]. In humans, no significant
differences were noted for the chemerin levels between
subjects with type 2 diabetes and normal controls. However,
in normal glucose-tolerant subjects, chemerin levels were
significantly associated with BMI, triglycerides, and blood
pressure [179]. Plasma chemerin levels in normal subjects
are also significantly associated with BMI, circulating triglycerides,
and blood pressure, suggesting a strong relationship
of this protein with obesity-associated complications [179].
It is possible that visceral fat may potentially contribute
to the chronic inflammation that is observed in obese
individuals. However, only a few studies have investigated
the adipokine concentrations in the portal circulation [180].
In order to be able to determine the physiological role
of chemerin in the glucose metabolism, and to identify
chemerin’s target tissues as well as relevant signal transduction
pathways, further studies will need to be undertaken.
5.8. Omentin, Apelin, Vaspin, and Retinol-Binding Protein
4 (RBP4). Omentin, which was originally referred to as
intelectin and first found in the intestinal Paneth cells, has a
predicted molecular weight of 33 kDa [181]. Omentin is a fat
depot-specific secretory protein synthesized by the visceral
stromal vascular cells, but not the adipocytes. It has also
been found in the human lung, intestine, and heart [182]
and is strongly expressed in the human ovaries and placenta
[183]. This new adipokine is codified by two genes (1 and 2)
and is highly and selectively expressed in the visceral adipose
tissue. In obesity, omentin 1 plasma levels and the adipose
tissue gene expression are decreased, and there is a positive
correlation with the plasma adiponectin and high-density
lipoprotein. These levels were negatively correlated with
waist circumference, BMI, and insulin resistance [184, 185].
Administration of glucose and insulin to human omental
adipose tissue explants resulted in a dose-dependent reduction
of the omentin-1 expression. Furthermore, prolonged
insulin-glucose infusion in healthy individuals resulted
in significantly decreased plasma omentin-1 levels [186].
Recombinant omentin enhances the uptake of glucose in
isolated adipocytes and dramatically increases the insulin
induction of Akt/PKB phosphorylation [182]. However,
further studies need to be undertaken, as the physiological
role of omentin in glucose metabolism along with omentin’s
target tissues, receptor, and the relevant signal transduction
pathways have yet to be determined.
Apelin is a bioactive peptide that is produced by
adipocytes, vascular stromal cells, the heart, and the cardiovascular
system [187]. In humans, both obesity and
insulin significantly elevate the plasma levels of apelin and
this peptide appears to act as a circulating and paracrine
hormone [187]. The gene that encodes the apelin, receptor
shares the greatest sequence identity with the angiotensin
AT1 receptor [187]. In experimental animal models of heart
failure, the cardiac apelin system is down-regulated by
angiotensin II, while restoration is achieved after treatment
with an angiotensin type 1 receptor blocker [188]. In the
cardiovascular tissues of rats, apelin production is upregulated
by hypoxia [189] and ischemic cardiomyopathy
[190], which perhaps may be a compensatory mechanism.
In spontaneously hypertensive rats, exercise training has also
been shown to up-regulate the apelin production [191].
Apelin has a positive hemodynamic effect, as it acts an
inotrope in both normal and failing rat hearts and in
isolated cardiomyocytes [192, 193]. Apelin may be able to
10 Mediators of Inflammation
regulate insulin resistance by facilitating the expression of
brown adipose tissue uncoupling proteins and by altering
adiponectin levels [194]. Decreased plasma apelin levels have
been observed in patients with lone atrial fibrillation [195]
and chronic heart failure [196]. Cardiac resynchronization
therapy has been used to treat these patients successfully,
with increases in the apelin levels observed after initiation of
the therapy [197].
Vaspin is a member of the serine protease inhibitor
family. This adipocytokine has been isolated from the
visceral adipose tissue of Otsuka Long-Evans Tokushima
Fatty (OLETF) rats that are at an age when the body
weight and hyperinsulinemia has peaked [198]. OLETF
rats are commonly used as a model of human type 2
diabetes. This model also shares common components of the
human metabolic syndrome, including abdominal obesity,
insulin resistance, hypertension, and dyslipidemia [199].
Vaspin production decreased at the same time the diabetes
worsened and body weight fell in the untreated OLETF rats.
However, when the animals were treated with insulin or
pioglitazone, serum vaspin levels were maintained [198].
This suggests that the up-regulation of vaspin may have a
defensive action against insulin resistance. Human vaspin
mRNA has been reported to be expressed in the visceral
and subcutaneous adipose tissue. In addition, it has been
shown to be regulated in a fat-depot specific manner, and
to be associated with obesity and parameters of insulin
resistance [200, 201]. It has also been reported that elevated
vaspin serum concentrations are correlated with obesity and
impaired insulin sensitivity, whereas type 2 diabetes appears
to abrogate this correlation [202, 203]. Vaspin expression
decreases in conjunction with a worsening of the diabetes
and a body weight loss. These studies indicated that vaspin
might play a causative role in the development of obesity
and metabolic disorders or, at least, be a biomarker for
these diseases. In order to clarify these potentialmechanisms,
further investigation using more sophisticated methods will
need to be undertaken.
Using the adipose-specific Glut4 knockout (adipose-
Glut4(−/−)) mice model, retinol-binding protein 4 (RBP4)
has been identified as a highly expressed circulating
adipokine that causes insulin resistance when it is overexpressed
or injected into mice [204]. In the circulation, RBP4
is bound to transthyretin, which causes decreases in the RBP4
renal clearance. In ob/ob mice, there was a 4-fold increase in
transthyretin plasma levels as compared to lean mice or dietinduced
obese mice [205]. A large number of subsequent
studies confirmed there was an association between increases
in the circulating RBP4 levels and various aspects of adiposity
[206], insulin resistance [207, 208], diabetes mellitus [209],
and metabolic syndrome [210, 211]. However, there are
also other studies that have been unable to establish these
associations [212, 213]. The reason for this discrepancy may
be explained in part by the different methods that were used
to measure the RBP4 and the different populations employed
in these various studies. In some very recent studies, it
has been reported that increased plasma RBP4 levels are
associated with inflammatory cardiomyopathy [214] and
cerebral infarction [215]. Therefore, at the current time,
whether RBP4 functions as an adipokine in humans and
exerts metabolic effects on glucose metabolism remains
uncertain. Further studies will need to be performed in order
to clarify RBP4’s exact role in humans.
6. Conclusions
The worldwide incidence of obesity has markedly increased
during recent decades. Obesity and associated disorders now
constitute a serious threat to the current and future health
of all populations on earth. Obesity represents a major
risk factor for diseases including CVD,,atherosclerosis and
diabetes, in which inflammation acts as a major driver in the
pathogenesis. Both adipocytes and macrophages within fat
tissue secrete numerous cytokines that may contribute to the
characteristic pathophysiological changes. By expanding our
knowledge on inflammation and the link between obesity
and CVD, this should make it possible to improve our
understanding of the pathophysiology of obesity.

Obesity is associated with increased cancer cell proliferation

Enhanced DEN-induced hepatocyte death, as observed in IKKβ- and p38α- liver specific
knockout mice (IkkβΔhep, p38αΔhep) or spontaneous liver damage in Nemo/IkkγΔhep mice is
associated with enhanced compensatory proliferation and augmented HCC development (Hui
et al., 2007; Luedde et al., 2007; Maeda et al., 2005; Sakurai et al., 2008). As mentioned above,
DEN administration to obese mice induced more liver damage than in lean mice. Nonetheless,
HCCs in obese mice exhibited reduced apoptotic cell death relative to HCCs in lean mice
(Figure 2A,B). Concurrently, HCCs in obese mice exhibited more proliferating cells than
HCCs in lean mice (Figure 2C,D), as well as elevated cyclin D1 mRNA expression (Figure
2E). Thus, despite the early increase in both DEN-induced apoptosis and compensatory
proliferation in obese mice given DEN at 16 weeks of age (Figure 2F), the long term effect of
obesity on HCC cell kinetics is to decrease cell death and enhance cell proliferation. These
findings suggest that alterations in signal transduction pathways that modulate hepatoma cell
proliferation independently of liver damage and compensatory proliferation may underlie the
tumor promoting effect of obesity especially at later time points.
To further examine this notion and separate effects of obesity on tumor growth and progression
from effects on tumor initiation, we transplanted established hepatoma cells (derived from a
DEN-induced HCC) into 2 months-old lean mice that were kept after tumor cell inoculation
on either LFD or HFD for 4 weeks. We also inoculated the same number of hepatoma cells
into 8 months-old mice that were kept on HFD for the preceding 6 months or were genetically
obese (LepOb). In all cases, tumor growth was monitored over the course of 4 weeks after
inoculation. The greater the degree of host obesity, the faster the tumors grew, reaching the
largest size in LepOb mice (Figure 3). We also treated some of the mice with the JAK inhibitor
AG490 (Eriksen et al., 2001) to inhibit STAT3 activation (see below). AG490 exerted a
stronger inhibitory effect on tumor growth in 2 months old mice kept on HFD than in mice
kept on LFD (Figure 3B,C) and as expected inhibited STAT3 phosphorylation (Figure 3D).
Obese HCC-bearing mice exhibit elevated STAT3 and ERK activation and liver inflammation
To identify signaling pathways responsible for enhanced hepatoma cell survival and
proliferation, we first examined the effect of obesity on several protein kinases known to be
affected by metabolic state. As expected (Tremblay et al., 2007; Um et al., 2004), obesity was
associated with decreased AKT phosphorylation and increased phosphorylation of the mTOR
target S6 kinase and its substrate ribosomal protein S6 (Figure 4A). This was observed in both
normal livers and HCCs, strongly suggesting that counter to a previous hypothesis (Calle and
Kaaks, 2004), AKT activation, driven by insulin or IGF-1, is unlikely to be responsible for
enhanced cell survival and proliferation in HCCs of obese individuals.
We next examined the effect of obesity on several signaling molecules affected by
inflammation and known to modulate HCC development (Hui et al., 2007; Maeda et al.,
2005; Sakurai et al., 2008; Sakurai et al., 2006). Consistent with previous findings (Hirosumi
et al., 2002; Solinas et al., 2007), obese mice exhibited elevated JNK activity in liver and even
a larger increase in JNK phosphorylation in HCCs (Figure 4B,C). HCCs in obese mice also
exhibited greatly elevated ERK phosphorylation relative to HCCs of lean mice, but p38
phosphorylation was not altered in obese liver and was even reduced in HCCs of obese mice
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(Figure 4B,C). Remarkably, both non-tumor liver tissue and HCCs from obese mice displayed
a substantial increase in STAT3 phosphorylation, indicative of activation of this oncogenic
transcription factor (Figure 4B,C).
Consistent with the increase in STAT3 activation, we found that obese mice exhibited elevated
circulating IL-6 (Figure 4D), a potent STAT3 activating cytokine (Kamimura et al., 2003).
Elevated IL-6 mRNA was observed in both non-tumor liver and HCCs of obese mice (Figure
4E). Obesity also enhanced expression of TNF and IL-1β mRNAs (Figure 4F,G). The amount
of TNF protein was also greatly elevated in normal liver and HCC from obese mice (Figure
4H). Elevated IL-6, TNF and IL-1β expression was also observed in obese female tumorbearing
mice (Figure S3A-D). Consistent with elevated inflammatory cytokines, livers from
obese mice contained higher amounts of macrophages and other leukocytes (Figure S3E-I).
Enhanced IL-6 production is required for obesity-induced tumor promotion
Given the marked increase in STAT3 phosphorylation and circulating IL-6 in obese mice and
their tumors, and knowing that IL-6 functions as a downstream mediator for both IL-1 and
TNF (Kamimura et al., 2003), we examined whether IL-6 is an important component of the
tumor promoting mechanism activated by obesity. To this end, we subjected WT and IL6-/-
mice to protocol #1 (Figure S1A), in which DEN is given to two weeks-old mice followed by
either LFD or HFD. Remarkably, IL6-/- male mice, which developed much fewer HCCs than
WT mice when kept on LFD, an observation consistent with previous findings (Naugler et al.,
2007), hardly exhibited any augmentation of tumor multiplicity, size and incidence when
placed on HFD (Figure 5A,B). Importantly, the HCC load in IL6-/- male mice is identical to
that of WT females (Naugler et al., 2007), but unlike WT females which produce more IL-6
when rendered obese (Figure S3A, B) and develop more HCC, no significant increase in tumor
load was seen in obese IL6-/- males (Figure 5C). Although IL6-/- males did not gain weight as
rapidly as WT males, they reached almost the same weight as WT mice after 8 months on HFD
(Figure 5D) and exhibited elevated serum TG (Figure 5E). IL6-/- males also showed increased
liver TG content after placement on HFD, although the extent of liver TG accumulation was
lower than in WT males. IL6-/- male mice also presented with elevated serum insulin after
placement on HFD, but the increase was not as robust as in obese WT males (Figure 5E).
These data suggest that obesity-associated chronic elevation in IL-6, a tumor promoting
cytokine whose expression can be induced by both TNF and IL-1, is an important contributing
factor to liver tumorigenesis.
To better understand how the absence of IL-6 prevents obesity-induced tumor promotion, we
examined its effect on stress/inflammation- and metabolism-responsive signaling molecules.
The absence of IL-6 prevented the obesity-induced increase in JNK and ERK phosphorylation
in non-tumor liver and HCCs and completely reversed the decrease in p38 phosphorylation
previously seen in HCCs of obese mice (Figures 5F and S4A; compare to Figures 4B and C).
As expected, the absence of IL-6 prevented STAT3 phosphorylation in liver and HCC of obese
mice (Figures 5F and S4A). Interestingly, the IL-6 deficiency also prevented much of the
obesity induced increase in S6 phosphorylation in both liver and HCCs and partially attenuated
the decrease in AKT phosphorylation (Figures 5F and S4A). These finding suggest that IL-6
is not only required for STAT3, ERK and JNK activation in the obese liver but that it also
contributes (indirectly, see below) to the alterations in AKT and mTOR-S6K signaling.
TNF receptor signaling is required for obesity-induced tumor promotion
In addition to IL-6, HFD increases expression of TNF, a pro-inflammatory cytokine that
stimulates IL-6 production. We previously found that TNF signaling via its type 1 receptor,
TNFR1, is not required for DEN-induced hepatocarcinogenesis in lean mice (Naugler et al.,
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2007). Nonetheless, given the dramatic increase in liver TNF production in obese mice (Figure
4H), we examined whether TNFR1 signaling contributes to obesity-induced tumor promotion.
Remarkably, ablation of TNFR1 almost completely abolished obesity-enhanced HCC
development without affecting HCC induction in lean mice (Figure 6A,B). TNFR1-/- mice,
however, gained almost as much weight as WT mice (Figure 6C). The rate of weight gain was
also very similar in the two strains.
Ablation of TNFR1 reduced JNK and p38 phosphorylation in both lean and obese mouse livers
and prevented the increase in JNK activity associated with HCC development (Figures 6D and
S4B). In addition, TNFR1-/- mice did not show the obesity-induced increase in STAT3 and
ERK phosphorylation. TNFR1 ablation also prevented the decrease in AKT phosphorylation
seen in HFD-fed WT mice and attenuated the changes in S6 phosphorylation (Figures 6D and
S4B).
TNFR1 signaling and IL-6 promote steatohepatitis
We further examined IL6-/- and TNFR1-/- tumor-bearing mice to identify a common mechanism
that could explain their resistance to obesity-induced tumor promotion. As expected, the
absence of TNFR1 reduced the obesity-induced increase in IL-6 production, resulting in lower
circulating IL-6 and less IL-6 mRNA in liver and in HCCs of obese mice (Figure 7A,B).
Conversely, the absence of IL-6 reduced the obesity-induced increase in TNF production in
tumor-bearing mice (Figure 7C). The absence of either IL-6 or TNFR1 in tumor-bearing mice
reduced HFD-induced liver lipid accumulation (Figure 7D,E). The absence of either IL-6 or
TNFR1 also reduced macrophage and neutrophil accumulation in livers of HFD-fed mice
(Figure 7F,G). We therefore conclude that both IL-6 and TNF signaling via TNFR1 are
important for liver lipid accumulation (hepatosteatosis) and fat-induced liver inflammation
(steatohepatitis), which together define NAFLD, a condition that greatly increases the risk of
HCC development (El-Serag and Rudolph, 2007; Parekh and Anania, 2007).
Discussion
Overweight and obesity greatly increase HCC risk, especially in men (Calle and Kaaks,
2004; Calle et al., 2003). Despite the magnitude of the effect and the very large number
(900,000) of individuals on which the epidemiological study that provided this insight was
based, the mechanisms by which obesity increases risk of death from HCC and other cancers
remained unknown. We now describe that genetic or dietary obesity greatly enhances the
development of chemically induced HCC in laboratory mice. By administering a chemical
carcinogen (DEN) to adult mice in which it fails to induce HCC on its own, we demonstrated
that obesity is a bona fide tumor promoter, whose effect is at least as strong as that of the
validated liver tumor promoter phenobarbital. Furthermore, we found that the tumor promoting
effect of obesity in HCC depends to a large extent on the low grade inflammatory response it
induces, which involves elevated production of TNF and IL-6, both of which are tumor
promoting cytokines (Lin and Karin, 2007).

Unadjusted associations among depression, obesity, and receiving screening

Lower education, smoking, and depressive symptoms were associated with fewer Paps and
mammograms received (Table 1). Increasing age, body dissatisfaction, and obesity were
associated with fewer Paps only while white, non-Hispanic race/ethnicity and never being
married were associated with less mammography.

Pathophysiology of acute lung injury and the possible role of obesity

A full description of the pathophysiology of ALI/ARDS is beyond the scope of the current
review and the reader is directed to recent reviews for further details (2;39). In brief, in ALI/
ARDS imbalances occur between pro- and anti-inflammatory cytokines, oxidants and antioxidants,
and coagulation factors. Alterations in neutrophil activation, recruitment and
clearance and release of proteases also are important. The net result of these changes is alveolar
filling with proteinaceous fluid, alveolar and interstitial edema, surfactant inactivation and
injury of the pulmonary microvascular bed.
Endothelial injury in the pulmonary microvasculature is a major contributor to the increased
permeability pulmonary edema of ALI/ARDS (40). Two mediators thought to play a role in
this endothelial dysfunction are endothelin-1 and von Willebrand factor (VWF). Endothelin-1
(ET-1) is released by endothelial cells in response to stress and injury, resulting in
vasoconstriction and inflammation (41). ET-1 is elevated in the plasma of patients with ALI/
ARDS, compared to healthy controls (42). VWF is also released in response to endothelial
activation and higher levels of VWF have been associated with increased mortality in ALI/
ARDS patients (43).
Plasma levels of ET-1 and VWF are both increased in non-critically ill obese patients. ET-1 is
released by subcutaneous adipose tissue and greater levels are secreted in obesity (44). VWF
is also increased in obesity (45) and appears to be linked to insulin resistance and endothelial
dysfunction (46). Despite this, it is unknown if ET-1 and VWF are increased in obese ALI/
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ARDS patients or if alterations in these pro-inflammatory mediators predispose obese patients
to the syndrome.
In addition to endothelial injury, ALI/ARDS is characterized by damage to the alveolar
epithelium. Characteristic lesions in the alveolar epithelium lead to loss of epithelial integrity
and result in pulmonary edema and impaired clearance of lung water. Injury to type II cells
leads to impaired surfactant production and lung repair (47). A comparison of the underlying
mechanisms of damage to the alveolar epithelium and the degree to which it occurs in obese
versus non-obese ALI/ARDS patients is lacking.
Neutrophils play a critical role in the development of ALI/ARDS with increased neutrophils
found in the lung and bronchoalveolar lavage fluid of ALI/ARDS patients (47;48). There are
a number of putative mechanisms thought to be involved in neutrophil recruitment and
activation, which may contribute to the development of ALI/ARDS, including up-regulation
of adhesion molecules, induced neutrophil deformation, release of neutrophil-derived
proteases and dysregulated neutrophil clearance (39). Alterations in neutrophil recruitment in
the obese ALI/ARDS patient may exist, but evidence is inconclusive. There appears to be an
increase in multiple adhesion molecule markers in the blood of obese patients, including
intracellular adhesion molecule-1 (ICAM-1) and E-selectin, which correlates with the degree
of obesity (49). However, other studies find that selected neutrophil adhesion antigens, such
as CD62L (L-selectin), are reduced in obese patients, suggesting the possibility of impaired
neutrophil recruitment (50). As with endothelial damage, we are unaware of studies directed
at differences in recruitment or activation of neutrophils in obese and non-obese ALI/ARDS
patients.
The inflammatory condition in ALI/ARDS is promoted and modulated by a complex interplay
of cytokines produced by a wide variety of cell types (51). Interleukin-1 (IL-1) and tumor
necrosis factor-α (TNF- α) are early response cytokines which promote subsequent
inflammation (39). IL-8 is thought to enhance this initial inflammation through recruitment of
neutrophils (52). These inflammatory markers are accompanied by anti-inflammatory
cytokines, such as IL-10 and IL-11, and inhibitors of pro-inflammatory cytokines, such as
soluble TNF receptors, IL-1 receptor antagonist and auto-antibodies against IL-8 (39). In
response to inflammatory stimuli, a number of cells release reactive oxygen and nitrogen
species which may be responsible for much of the cellular damage occurring in ALI/ARDS
(53).
Data linking obesity and ALI/ARDS is, perhaps, most convincing on the basis of chronic
excessive inflammation and oxidative stress in obese patients compared to nonobese patients
(54). There is a significant increase in abnormal cytokine production and acute-phase reactants
and an up-regulation of pro-inflammatory signaling pathways in otherwise-healthy obese
patients (55). Additional weight gain stimulates further induction of pro-inflammatory
cytokines and mediators, such as TNF-α, IL-6, pre-B-cell-enhancing factor (PBEF),
plasminogen activator inhibitor -1 (PAI-1), angiotensinogen, retinol-binding protein-4
(RBP-4), leptin, and IL-1β (54). In fact, adipose cells can contribute up to 30% of circulating
IL-6 in obese individuals (56).
Obesity is associated with an increase in oxidative stress and formation of reactive oxygen
species (57). Reactive oxygen species cause cellular injury through direct damage to cellular
membranes and by cellular adhesion of monocytes and release of chemotactic factors and
vasoactive substances (58). Oxidative stress has been associated with diaphragmatic
dysfunction (59). Diaphragmatic dysfunction has also been described in obesity (60) but a
direct link between oxidative stress, obesity and diaphragm function has not been reported.
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Adipocytokines and ALI/ARDS
In addition to classic cytokines, adipose tissue releases adipocytokines which act as mediators
of subsequent pro-inflammatory and anti-inflammatory pathways (54). While there are a
number of known adipocytokines, of primary importance are leptin and adiponectin (54).
Leptin is a polypeptide hormone secreted by adipocytes which is elevated in states of obesity
and functions as a mediator of energy balance (61). It is secreted mainly by adipose tissue and
meant to signal adequate stores of energy and feelings of satiety. When energy levels diminish,
leptin levels fall to stimulate feelings of hunger. Leptin levels are increased in patients with
obesity and are thought to play a role in the development and maintenance of obesity and its
morbid complications. These increased levels may be a result of leptin-resistance, which is
present in more than 90% of patients with type II diabetes and is believed to be due to receptor
down-regulation (62).
In addition to its regulation of energy balance, leptin also functions as an adipocytokine to
affect inflammatory cells. Leptin can induce the production of TNF-α, IL-1β, IL-1RA, IL-R2,
and IL-6 as well as that of reactive oxygen species, and to increase phagocytosis in some antigen
presenting cells (63). Leptin has a structural similarity to other cytokines, such as IL-6, which
is known to serve a pro-inflammatory role. However, leptin’s role in acute inflammatory
conditions leading to ALI/ARDS, such as sepsis, is unproven. For example, in normal
volunteers, plasma leptin is not increased above baseline after intravenous endotoxin
administration at 6 or 24 hours (64). Similarly, studies exploring an association between leptin
levels and outcomes from sepsis are conflicting. One showed an association between elevated
leptin levels and higher mortality (65), another found no association (66), and others showed
higher leptin levels in sepsis survivors (67;68).
One recent study attempted to evaluate the role of leptin and leptin resistance and its potential
protective properties in mice with hyperoxia induced acute lung injury (69). With hyperoxia,
lung leptin levels were increased in wild-type and leptin-receptor deficient mice. However,
leptin resistant mice developed less lungedema and lung injury and had improved survival
compared to mice with normally functioning leptin receptors. This suggests that the activation
of the leptin receptor plays a role in the development of acute lung injury from hyperoxia and
leptin resistance may be protective in preventing acute lung injury and associated morbidity
and mortality. The relevance in alternate models of ALI/ARDS and in patients with ALI/ARDS
is unknown.
Patients with diabetes mellitus, many of whom have elevated leptin levels, appear to be
protected from acute lung injury. Several studies have suggested that diabetic patients are at
lower risk for developing ARDS when suffering an acute insult associated with ALI/ARDS
(70;71). It is unknown if this apparent protection from ALI/ARDS in diabetic patients at risk
is due to an effect of leptin resistance, excess weight or alternate mechanisms.
Adiponectin is another adipocytokine that might play a role in the pathogenesis of ALI/ARDS
of obese patients. It stimulates fatty acid oxidation, decreases plasma triglyceride levels, and
improves insulin sensitivity (72). Adiponectin levels are generally decreased in obese
individuals (73). Adiponectin has anti-inflammatory effects, including suppression of TNF-
α, IL-6 and nuclear factor-κB and up-regulation of IL-10 and IL-1RA (74).
Studies using animal models (most commonly transgenic rodents with dysfunctional leptin
receptors) have begun to explore a possible interaction between obesity and acute
inflammation. In an experimental model of acute pancreatitis, pulmonary levels of TNF-α
mRNA were significantly higher in obese than lean rats. However, there were no significant
differences in pulmonary mRNA levels of IL-6, IL-10, or pancreatitis-associated protein
(75). In a study exploring bronchial hyper-responsiveness seen in obese mice lacking the leptin
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receptor, investigators measured bronchoalveolar (BAL) levels of cytokines and
adipocytokines (76). There were minimal differences between the wild-type and transgenic
mice in regards to BAL inflammatory cytokines. However, BAL leptin levels were higher in
obese than lean mice and there was a trend toward lower adiponectin levels in the obese mice.
It remains unknown if these differences might also affect the murine response to stimuli causing
ALI/ARDS.
Obesity and Outcomes from Acute Lung Injury
While a number of studies explore the association between obesity and outcome for critically
ill adults (see article in this issue by Honiden and McArdle), few articles have focused
specifically on patients with ALI/ARDS (see Table 2). The first such study (77) reported a
secondary analysis of patients enrolled in the National Heart, Lung and Blood Institute’s
(NHLBI) multicenter, randomized trials of the Acute Respiratory Distress Syndrome Network
(78–80). These studies included comparisons of lower and higher tidal volumes (6 ml/kg versus
12 ml/kg predicted body weight, respectively) and ketoconazole or lisofylline versus placebo.
Of note, patients with a weight-to-height ratio (kilograms divided by centimeters) of >1.0 were
excluded from these studies. BMI calculated from height and weight at the time of study
enrollment was used as the measure of excess weight with a variety of variable formats used
in the analyses. Risk-adjusting methods incorporated multi-variable logistic regression with
survival to 28 days being the primary outcome.
BMI data were missing for 6.1% (n=55) of subjects enrolled in the initial studies. The
investigators also excluded subjects with an underweight BMI (<18.5 kg/m2, 4.7%, n=40).
Ultimately, 807 subjects were included in the analysis. Based on NHLBI categories of BMI,
31.5% (n=254) of subjects had an overweight BMI and 27.1% (n=219) had an obese BMI. In
unadjusted analyses, there were no significant differences in 28-day or 180-day mortality,
achieving unassisted ventilation by day 28 or ventilator-free days between patients with
overweight or obese BMIs and those with normal BMIs. After adjusting for the effects of age,
severity of illness, PaO2/FiO2 ratio, study group assignment, peak airway pressure, primary
lung injury category, and gender, there was no significant increase in the adjusted odds of 28
day mortality for subjects with overweight (adjusted odds ratio 1.10 [95% confidence interval
0.71 – 1.69]) or obese BMIs (adjusted odds ratio 1.11 [95% confidence interval 0.69 – 1.78]),
compared to subjects with normal BMIs. There was also no significant association in
multivariable analysis including BMI as a continuous variable, when severe obesity (BMI ≥
40kg/m2) was considered or when the subject’s BMI was adjusted for the fluid balance for the
24 hours preceding study enrollment. The same risk-adjusting model was refit for 180-day
mortality, achieving unassisted ventilation by day 28, and ventilator-free days. In no analysis
were overweight or obese BMIs associated with outcomes.
A second retrospective study by the same authors used data from Project IMPACT®, a
subscription database designed for ICU benchmarking
(www.cerner.com/piccm/products_pi.html), to further explore any possible association
between obesity and outcomes among ALI patients (81). The investigators analyzed data from
1488 patients admitted from December 1995 to September 2001. Subjects were included if
(1) admission data allowed for a BMI calculation, (2) there was an admission diagnosis
consistent with ALI and (3) the subject required mechanical ventilation within 24 hours of
intensive care unit (ICU) admission. Again, BMI was used as an indicator of excess weight
and was calculated from data included in the admitting record. The primary outcome was
hospital mortality and multivariable logistic regression was used to account for possible
confounding. Underweight patients were included in the analysis.
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Of the included subjects, 26.8% (n=399) had an overweight BMI, 21.9% (n=326) had an obese
BMI, and 8.8% (n=131) were severely obese, by NHLBI categorization (82). In unadjusted
analyses, there was a significant association between BMI and hospital mortality (p<0.001).
Crude hospital mortality was highest in patients with underweight BMIs (54.6%) and lowest
in the severely obese patients (29.0%). Hospital mortality was intermediate in the other BMI
categories. ICU and hospital length of stay and discharge destination were not different between
the various BMI categories. The best fit of the non-categorized BMI variable with hospital
mortality was found to be a quadratic transformation and this was also significantly associated
with hospital mortality in unadjusted analyses (p<0.0001). After adjustment for an assortment
of possible confounders found in preliminary analyses, BMI category remained associated with
hospital mortality (p<0.0001) when the group with normal BMIs were considered the referent
group. The highest adjusted odds for mortality were in the patients with underweight BMIs
(adjusted odds ratio 1.94 [95% confidence interval 1.05 – 3.60]) and patients with an obese
BMI had significantly lower adjusted odds of death (adjusted odds ratio 0.67 [95% confidence
interval 0.46 – 0.97]). A trend toward lower mortality for the overweight and severely obese
BMI groups was also suggested in risk-adjusted analyses (adjusted odds ratios, 0.72 and 0.78,
respectively) but failed to reach statistical significance. A similar association was observed
when the transformed BMI variable was included in the risk-adjusting model with the highest
adjusted odds seen at underweight BMI levels and the lowest odds seen at a BMI of 35–40 kg/
m2.
The most recent study examining the association between obesity and acute lung injury used
data gathered as part of a population-based, prospective cohort study among 21 hospitals in
and around King County, Washington between April 1999 and July 2000 (KCLIP) (3). All
patients receiving mechanical ventilation in the participating hospitals were screened for
enrollment based on the American-European Consensus Conference definition of ALI (1). In
the analysis of this data examining obesity (83), BMI was calculated from height and weight
recorded at hospital admission and NHLBI categories were utilized. Outcomes included ICU
and hospital mortality, ICU and hospital length of stay, duration of mechanical ventilation and
discharge disposition. Multivariable logistic and linear regression models were used for riskadjusting.
As in the prior studies examining excess weight and ALI, the majority of subjects were either
overweight (28.7%, n=237) or obese (28.7%, n=237). Crude mortality was highest in the
patients with underweight BMIs (44.0%) and decreased as BMI increased. ICU and hospital
lengths of stay and duration of mechanical ventilation were similar among all BMI categories
in unadjusted analyses. After adjustment for age, severity of illness and ALI risk factor, there
were no statistically significant differences in mortality between the underweight, overweight,
obese or severely obese BMI groups and the reference group (patients with normal BMIs). ICU
and hospital lengths of stay were markedly increased among the severely obese patients (BMI
≥ 40) compared to patients with normal BMIs. Moreover, compared to survivors with normal
BMIs, the risk-adjusted duration of mechanical ventilation among surviving severely obese
patients was increased by 4.1 days (95% confidence interval 0.4 to 7.7 days). Finally, severely
obese patients were more likely to be discharged to rehabilitation facilities and skilled nursing
facilities. These differences in lengths of stay, duration of ventilation and discharge location
among the severely obese were not observed among the patients with overweight and obese
BMIs compared to those with normal BMIs.
Obesity as a Risk Factor for Acute Lung Injury and Multi-Organ Failure in At-
Risk Patients
Because of changes in physiology and inflammation associated with excess weight, it is
conceivable that obese patients might be at greater risk for ALI/ARDS when suffering a
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predisposing acute event, such as sepsis or trauma. One of the earliest studies exploring an
association between obesity and outcome among the critically ill reviewed data from 184
patients admitted to a trauma service over six months (84). In this study, mortality was
significantly higher in patients with a BMI>31 kg/m2 (42.1% versus 5.0% in patients with
BMI<27) and this increased mortality remained after adjustment for severity of injury. The
authors also noted that the higher BMI group had a significantly higher rate of complications
per patient and this “was predominantly accounted for by an increase in pulmonary
complications.” The details of these pulmonary complications were not provided. However,
the authors also presented the cause of death among the 17 patients who died. Seven of eight
higher BMI patients had ARDS listed as the primary factor leading to death. No patients in the
lower BMI group (BMI <27) had ARDS listed as the primary factor leading to death, although
3 of 6 had multi-organ system failure listed.
A more recent retrospective cohort study re-explored this association among 242 consecutive
patients admitted to an intensive care unit following blunt trauma (85). There were no
differences in the development of ARDS between subjects with an obese (BMI≥30kg/m2) or
a non-obese BMI (8% vs. 6%, p=0.55) but obese subjects had a higher rate of multi-organ
system failure (13% vs. 3%). After adjustment for head injury, pulmonary contusion, injury
severity and age, the subjects with obese BMIs had significantly higher mortality (adjusted
odds ratio 5.7 [95% confidence interval 1.9 – 19.6]). However, only one death in the study was
attributed to respiratory failure. Multi-organ system failure was a more common cause of death
among the obese-BMI subjects than the non-obese-BMI subjects (35.0% vs. 17.2%).
A secondary analysis of a prospective cohort study of critically injured adults sought to
determine if obese and severely obese patients were at increased risk of pulmonary
complications, including ARDS (86). The study cohort included 1219 adults admitted to an
ICU following trauma. ARDS occurred in 21% of normal-BMI patients, 32% of obese-BMI
patients and 11% of severely obese-BMI patients. After adjustment for age, gender and severity
of injury, the patients with severe obesity had a statistically significant decrease in the risk of
ARDS (adjusted odds ratio 0.36 [95% confidence interval 0.13 – 0.99]) compared to the
normal-BMI group. A similar effect was not seen amongst the overweight- (adjusted odds ratio
0.97) and obese-BMI groups (adjusted odds ratio 1.0). When BMI was explored as a continuous
variable, the peak of unadjusted risk for ARDS occurred between a BMI of 20 and 30.
Ventilator management practices, including tidal volume, were not reported.
While there are hypothetical reasons that obesity could create a pathologic milieu promoting
the development of ALI/ARDS in patients otherwise at risk, definitive data are lacking. Most
studies have focused on less specific outcomes such as length of stay and mortality for obese
ICU patients. As discussed subsequently, even those studies focusing on the development of
ALI/ARDS in obese patients suffer from potential bias due to the definition of ALI/ARDS and
lack of standard care practices.
Limitations of Human Studies Exploring an Association between Obesity and
Acute Lung Injury
Measures of excess weight and the heterogeneity of obesity
Existing studies of excess weight and ALI have only examined BMI as the measure of excess
weight. While this measure is highly reliable and associated with adult body fat in ambulatory
patients (87), BMI might not be the best representation of risk (or benefit) for critically ill
patients. For example, the distribution of excess weight may have particular relevance for
mechanically ventilated patients kept in a supine or semi-supine position (88). In selected
epidemiologic studies, waist circumference is a better marker of cardiovascular risk than BMI
McCallister

Obese children have more respiratory symptoms than their

normal weight peers and respiratory related pathology
increases with increasing weight. Some will need specialist
assessment (box 1). Obesity produces mechanical effects
on respiratory system performance. Breathlessness,
wheeze, and cough are not related to increased airway
responsiveness and may respond more to weight loss than
bronchodilator therapy. A significant number of obese
children have signs and symptoms of obstructive sleep
apnoea largely related to the effect of obesity on upper
airway dimensions. It seems likely that unless action is
taken soon,34 increasing numbers of children will
experience preventable respiratory morbidity as a result of
nutritional obesity
BACO KO HA REVIEW
Obesity and the pulmonologist
S Deane, A Thomson

Role of leptin in melanoma growth

When tumor weight was expressed as a percentage of body weight, melanoma tumors from
MC4R−/− mice, which had high levels of leptin, were significantly larger than tumors from
other groups of mice (Fig. 1B). Pair feeding of leptin deficient ob−/− mice resulted in body
weights that were not different from those of WT mice (30.5 g for the pair fed ob−/− vs. 29.7
g for WT). However, melanomas in pair-fed ob−/− mice were only half the size of those from
lean WT. These observations indicate that while leptin is not required for melanoma growth,
leptin deficiency greatly attenuates tumor growth while increased levels of leptin may modestly
increase tumor growth.
Tumors express leptin receptors but not leptin
Leptin has been proposed to act in an autocrine or paracrine manner on endothelial cells to
promote angiogenesis. We measured leptin levels in the plasma and tumors of the different
groups of mice, and in the cell culture medium from B16F10 cells to determine whether these
melanoma tumors produce leptin. Plasma leptin in obese MC4R−/− mice was 37.9 ng/mL,
compared to 2.4 and 2.9 ng/mL in non-obese WT and obese ob+/− mice, respectively (Table
1). These levels are similar to those previously reported for these mice. 13,14 In the plasma of
ob−/− and pair fed ob−/− mice, leptin was below detectable limits of the assay.
Tumor leptin levels were very low and appeared to reflect host circulating leptin levels, with
the highest leptin found in tumors from MC4R−/− mice, followed by WT and ob+/− tumors
(Table 1). Leptin was undetectable in the tumors from ob−/− and pair fed ob−/− mice. We were
also unable to detect leptin in the medium from cultured B16F10 cells. These observations
suggest that very little or no leptin is produced by mouse melanoma tumors.
Leptin receptor expression in tumors of the different groups of mice and in B16F10 cells was
measured by western blot. The leptin receptor was expressed in all melanoma tumors and in
B16F10 cells (Fig. 2A). Leptin receptor expression in the tumors was not different among the
five groups of mice (Fig. 2B). 3H-thymidine incorporation assay showed that human leptin
(100 ng/ml) slightly (10.4%) but significantly increased the proliferation of cultured B16F10
cells (Fig. 2C). These observations indicate that the lepin receptor in B16F10 cell is functional.
Tumors from obese mice are more necrotic
Upon dissection at the end of the study, 70–80% of the tumors taken from obese mice were
surrounded by blood and pus, whereas the percentage was less than 43% in the tumors from
lean mice. Necrosis was examined in haematoxylin and eosin stained tumor cross sections.
Overall, the larger tumors were more necrotic. Ob−/− tumors had the most necrosis and were
followed by MC4R−/− tumors (Fig. 3A and B). While WT and ob+/− tumors had similar levels
of necrosis, tumors from pair fed ob−/− mice had the least amount of necrosis.
Obesity increases expression of VEGF and its receptors
In plasma taken from mice at the time of sacrifice, VEGF was highest in MC4R−/− mice, while
WT mice had the lowest VEGF (Fig. 4A). There were no differences in plasma VEGF among
ob+/−, ob−/− and pair fed ob−/− mice. However, pair feeding in ob−/− mice significantly
increased VEGF production in comparison to WT mice.
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We measured the expression of VEGF and its two receptors, VEGF-R1 and R2, in the
melanoma tumors to determine the effects of obesity and leptin on these angiogenic factors.
VEGF expression was increased in the tumors of obese leptin deficient ob−/− mice, as well as
in tumors of obese MC4R−/− mice. In contrast, lean WT, pair fed ob−/− mice, and ob+/− mice
expressed low levels of VEGF protein (Fig. 4B). There were no differences in tumor VEGF
levels between tumors obtained from leptin-deficient and leptin-replete mice. Thus, tumor
VEGF levels were highly correlated with tumor size regardless of host leptin (Fig. 4C).
The expression of VEGF receptor 1 and 2 was examined in the melanomas by ELISA. Both
receptors were proportional to tumor size, except for the ob+/− tumors, which expressed the
receptors similarly to obese MC4R−/− and ob−/− tumors (Fig. 4D and E).
Obesity increases tumor blood vessel growth
We also examined blood vessels in the mouse melanomas using immunohistochemistry for
the endothelial cell marker, CD31. Blood vessels formed in the tumors from all groups of mice
and appeared as elongated and punctuated structures throughout the tumor. Nine cross sections
from each tumor were examined for CD31 staining. Because the amount of necrosis was
different in each group of melanomas, blood vessels were counted in at least twenty randomly
obtained images and expressed as the number of CD31-stained areas touching points in a grid
overlay out of the total number of points touching the tumor. The highest density of blood
vessels in all tumors was seen on the side of the tumor touching the dorsal body wall. CD31
staining was proportional to tumor size. MC4R−/− and ob−/− melanomas appeared to have a
highest percentage of CD31 staining followed by WT, ob−/− pair fed, ob−/− and ob+/− mice
(Fig. 5), and there was a significant difference between the wild-type and two obese groups,
MC4R−/− and ob−/− (p < 0.05).
Discussion
Important new findings of this study are that (1) obesity promotes melanoma tumor growth,
regardless of the presence or absence of leptin; (2) energy restriction greatly attenuates tumor
growth in obese mice; (3) leptin, although not essential for melanoma tumor growth, may
accelerate tumor growth while leptin deficiency in the absence of obesity attenuates tumor
growth; (4) leptin receptors are expressed in mouse melanoma cells and leptin slightly but
significantly increases the proliferation of cultured B16F10 cells, as assessed by DNAsynthesis
assay. We also found that tissue VEGF levels were much higher in the melanomas
from obese mice and that tumor VEGF was independent of host plasma leptin or circulating
VEGF levels.
While epidemiological studies suggest a positive correlation between body mass index and the
risk of certain cancers (e.g., colon, breast, renal cell and uterine cancers) no clear cause and
effect relationship has been previously established.3,15 Until recently, there had been no studies
that have examined the relationship between obesity and the incidence of melanoma. Our
finding that melanomas from obese MC4R−/− mice with high levels of leptin and obese
ob−/− mice with leptin deficiency grew much faster than melanomas from lean WT or lean
ob −/+ mice suggests that obesity was a major factor in determining tumor growth even in the
absence of leptin. Moreover, restriction of energy intake to prevent obesity in ob−/− mice greatly
reduced tumor size to levels below those observed in lean WT mice, further supporting a key
role for excess energy intake and obesity in stimulating melanoma tumor growth.
Angiogenesis is required for adipose tissue expansion during weight gain and a direct
relationship between obesity and angiogenesis was demonstrated by experiments in which
angiogenesis inhibition prevented obesity and caused weight loss in genetically obese mice.
16 One mechanism by which obesity has been suggested to contribute to enhanced tumor
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growth is by promoting angiogenesis. Our finding that plasma VEGF was significantly higher
in obese MC4R−/− mice, compared to WT mice, supports a role for enhanced angiogenesis in
these mice. However, there were no significant differences in plasma VEGF among obese
ob−/− mice with high rates of tumor growth and lean ob+/− and pair fed ob−/− mice with much
lower rates of tumor growth.
The use of a pair fed ob −/− group in this study was intended to prevent obesity in the leptindeficient
mice so the impact of leptin deficiency could be assessed independently of increased
body weight. Our observation that energy restriction greatly reduced melanoma tumor growth
is consistent with previous findings that chronic or intermittent caloric restriction may slow
the growth of other types of cancers, such as mammary tumors.17,18 The mechanisms that
mediate the effects of food restriction on tumor growth are unclear but likely involve numerous
metabolic pathways, including those involved in angiogenesis. The lower rates of melanoma
tumor growth observed in pair fed ob−/− mice relative to WT mice of similar body weight,
despite higher levels of VEGF in the pair fed ob−/− mice, could result from increased production
of antitumorigenic factors during food restriction that inhibit melanoma growth. This
observation is surprising and raises important questions for future research.
Our results also suggest that while leptin is not required for melanoma growth, it may play at
least a partial role in amplifying tumor growth. Ob −/− mice fed ad libitum were significantly
more obese than MC4R−/− mice, but had similar VEGF expression and tumor sizes. If leptin
had no effect on tumor growth, we would expect larger tumors in the obese ob−/− mice, since
these mice are 38% heavier than the MC4R−/− mice. Moreover, in lean, pair fed leptin deficient
ob−/− mice, melanomas were half the size of tumors from lean WT or ob+/− mice, which have
similar body weights but higher leptin levels. These observations suggest that leptin deficiency
greatly attenuates melanoma tumor growth while high leptin levels may accelerate tumor
growth.
The mechanisms for leptin’s effects on tumor growth are still uncertain, although a role for
leptin in promoting angiogensis has been previously suggested. Results from one study
demonstrated that treatment with leptin induced neovascularization in the corneas of normal
rats but not in the corneas of obese Zucker fa/fa rats, which have a mutation in the leptin
receptor.19 In addition, leptin has been shown to interact synergistically with fibroblast growth
factor 2 (FGF-2) and VEGF, two potent and commonly expressed angiogenic factors, to
stimulate angiogenesis in corneal explants.20 In this study, we were unable to detect leptin in
the medium from cultured B16F10 cells. These observations suggest that very little or no leptin
is produced by mouse melanoma tumors. However, the leptin receptor was expressed in all
melanoma tumors and in B16F10 cells. It is possible that leptin can interact with VEGF to
promote the growth of melanoma tumors.
There is indirect evidence from clinical studies that leptin may enhance tumor growth by
stimulating angiogenesis. For example, leptin expression correlated well with VEGF
expression in human gastric cancers and both factors were associated with poor patient
prognosis.21 Results from a recent study in mice showed that mammary tumor VEGF, VEGFR2
and tumor growth were significantly reduced when mice were treated with the leptin
receptor antagonist, LPrA2.11 While we found that VEGF and VEGF receptor expression was
well correlated with melanoma size, they were not well correlated with leptin levels. Thus,
leptin may interact with VEGF to promote growth of some cancers, but not others.
Leptin has been identified in several types of human cancers and may also be linked to poor
prognosis. In two studies, leptin and leptin receptor expression were significantly increased in
primary and metastatic breast cancer relative to noncancerous tissues in women. 22,23 In a
clinical study of colorectal cancer, leptin expression was positively correlated with tumor G2
Brandongrade.24 Serum leptin and leptin receptor expression in renal cell carcinomas was well
correlated with progression-free survival, venous invasion and lymph node metastasis.25
Leptin has also been shown to be expressed in uterine and endometrial cancers. 26 However, it
is difficult to dissociate the direct effects of leptin from other effects of obesity in these studies;
increased adiposity has important metabolic effects and stimulates release of many cytokines,
inflammatory mediators and factors other than leptin that could promote tumor growth.
There is very little previous information on the relationship between leptin and melanoma. One
epidemiological study reported that high serum leptin was positively correlated with melanoma
risk.27 However, to our knowledge there have been no previous studies that have examined
leptin or leptin receptor expression in melanoma tumors. Results from the single animal study
published found no differences in the incidence of skin papillomas induced by 7,12-
dimethylbenz(a)anthracene between obese ob−/− and lean ob+/− mice.28 Our results indicate
that while leptin receptors are expressed in melanoma tumors, the melanoma cells do not appear
to produce leptin. In leptin deficient ob−/− mice, leptin measured in the tumors was barely
detectable, whereas in MC4R−/− mice with high plasma leptin levels, the amount of leptin
extracted from the tumors was markedly elevated compared to that of WT and ob+/− tumors.
The leptin in these tumors likely derives from host leptin that is sequestered in the tissues from
the circulation or from immune cells that infiltrate the tumor.
Epidemiological studies suggest that hyperglycemia and hyperinsulinemia are associated with
increased risk for development of cancer.29 In the present study, we found that pair fed
ob −/− mice had the smallest tumors in comparison with tumors from the other groups of mice
even though they had high plasma glucose levels. These findings suggest that hyperglycemia
alone does not increase melanoma tumor growth in this in vivo model. Although we do not
have insulin data, we previously reported that MC4R −/− mice had several-fold greater plasma
insulin levels than WT mice.13 Additionally, other investigators have published plasma insulin
levels in ob −/− mice and found them to be significantly higher than lean wild type mice. 30
However, further studies are needed for testing the hypothesis that hyperinsulinemia increases
tumor growth in this model of melanoma.
Tumors from obese mice are more necrotic
The observation of increased necrosis in tumors from both groups of obese mice is in line with
what is expected in a model such as this. Mice were injected with a large number of cells that
grow rapidly. Ten days after injection, nearly all of the mice had palpable tumors and by
experimental day 17, some tumors were more than four centimeters in diameter. Most of the
necrotic areas were concentrated in the center of the tumors where the diffusion of nutrients
from blood vessels would not be reduced. The small percentage of necrosis in pair fed ob −/−
tumors suggests that tumor angiogenesis kept pace with tumor growth.
Obesity increases tumor angiogenic factor expression
The expression of VEGF in tumors is well correlated with tumor size and we found that VEGF
levels were much higher in the melanomas from obese mice. Tumor VEGF was independent
of host plasma leptin levels.
Except for ob+/− melanomas, the expression of VEGF-R1 and R2 was also proportional to the
size of the melanoma. A possible explanation for this is that VEGF is very low in ob+/− tumors
compared to VEGF in the tumors from other lean groups, which may have caused upregulation
of VEGF-R1/R2 expression in an effort to boost VEGF signaling. The body weights, plasma
leptin levels, and tumor sizes were similar between ob+/− and WT mice, thus the differences
in tumor VEGF receptor expression were surprising.

KALO MAU TAU PENYEBAB OBES PADA ANAK SAMA PNGOBATANNYA BACA INI

Pediatric Obesity: Etiology and Treatment

Purpose of review—Obesity is established as an important contributor of increased diabetes

mellitus, hypertension, and cardiovascular disease, all of which can promote chronic kidney disease
(CKD). Recently, there is a growing appreciation that even in the absence of these risks, obesity itself
significantly increases CKD and accelerates its progression.
Recent findings—Experimental and clinical studies reveal that adipose tissue, especially visceral
fat, elaborates bioactive substances that contribute to the pathophysiologic renal hemodynamic and
structural changes leading to obesity-related nephropathy. Adipocytes contain all the components of
the renin-angiotensin-aldosterone system, plasminogen activator inhibitor, as well as adipocytespecific
metabolites such as free fatty acids, leptin, and adiponectin which affect renal function and
structure. In addition, fat is infiltrated by macrophages that can alter their phenotype and foster a proinflammatory
milieu which advances pathophysiologic changes in the kidney associated with
obesity.
Summary—Obesity is an independent risk factor for development and progression of renal damage.
While the current therapies aimed at slowing progressive renal damage include reduction in weight
and rely on inhibition of the renin-angiotensin system, the approach will likely be supplemented by
interventions aimed at obesity-specific targets including adipocyte-driven cytokines and
inflammatory factors.
Pathophysiology
Obesity induces several pathophysiologic disturbances that contribute to renal injury.
Renin-angiotensin-aldosterone system (RAAS)
The RAAS is a major regulator of vasomotor tone and cellular proliferation that affect renal
function and structure. Adipocytes and adipose-infiltrating macrophages comprise an
important source of RAAS (Figure 2). Indeed, visceral fat expression of angiotensinogen (Aog)
approximates that of the liver, classically considered the chief source of Aog.[26] Circulating
levels of Aog increase with increasing BMI.[27] Relevant to obesity and CKD, infusion of
angiotensin II (AngII) in obese mice resulted in a dramatic increase in adipocyte-derived and
circulating, but not liver, Aog.[28] The AngII type 1 receptor (AT1), primarily responsible for
post-glomerular vasoconstriction, is elevated in the renal cortex of obese Zucker rats.[29] Renal
AT1 is also upregulated in transgenic mice overexpressing Aog exclusively in adipocytes (aP2-
Agt).[30] Overall, adipose-derived increase in circulating RAAS ligands together with
adipose-driven increase in renal AT1 provide a powerful combination for increasing efferent
arteriolar vasoconstriction, glomerular pressure, FF, as well as cellular proliferation that
culminate in renal damage. As with other proteinuric glomerulopathies, inhibition of RAAS
has been used to treat ORG. Notably, although escape from the antiproteinuric benefits of
angiotensin converting enzyme inhibition has been observed, it coincided with weight gain,
further underscoring the prominent role of adipose tissue RAS.[31] Fasting decreases Aog and
can reduce AngII production and AT1 density.[26] Such mechanisms may have contributed
to decreased proteinuria observed in an obese teenager soon after bariatric surgery with
negative caloric balance but minimal weight loss.[32]
Less easily conceptualized is the role of the AngII type 2 receptor (AT2). Obese Zucker rats
treated with an AT2 receptor antagonist showed dramatic increase in blood pressure and renal
cortical renin.[33] Similarly, when AT2 null mutation was introduced into the aP2-Agt strain
of mice overexpressing Aog in adipocytes, exacerbation of hypertension, higher renal renin,
and higher circulating AngI were observed.[34] AT2 KO/ aP2-Agt mice showed significant
amelioration of elevated adipocyte levels of several angiogenic/inflammatory cytokines than
aP2-Agt mice with intact AT2, including TNF-α, IL-6, IL-1β, and vascular endothelial growth
factor (VEGF). These data thus suggest a role for AT2 in mediating the considerable adipose
inflammatory response associated with increased Aog.[34]
Aldosterone blockade lessens renal injury. These benefits are independent of antihypertensive
effects and instead, may relate to blocking aldosterone effects on plasminogen activator
inhibitor (PAI-1) and transforming growth factor-β (TGF-β̣, reactive oxygen intermediates,
inflammatory mediators, and podocyte function.[35] [36] [37] Adipose tissue is capable of
AngII-independent aldosterone production and at least one oxidized derivative of linoleic acid
is able to stimulate aldosterone production.[38] Further, complement-C1q TNF-related protein
1 (CTRP1), which in part mediates AngII stimulation of aldosterone, is also prominently
expressed by adipose tissue where it may mediate AngII-independent aldosterone production.
[39] Treatment with eplerenone in a mouse model of metabolic syndrome increases podocyte
nephrin, reduces proteinuria and normalizes urinary markers of oxidative stress.[35] In this
connection, the transgenic Ren2 rat shows podocyte foot process effacement which is
normalized by treatment with spironolactone accompanied by a reduction in albuminuria as
well as attenuating NADPH oxidase activity.[40] Overall, elevated aldosterone which prevails
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in obesity may be injurious to glomeruli through indirect effects to increase GFR as well as
through direct podocyte effects.
Plasminogen activator inhibitor-1 (PAI-1)
PAI-1, as the primary physiological inhibitor of plasminogen activators, inhibits fibrinolysis
and proteolysis and has a key role in obesity and insulin resistance. [41,42] [43] [44] Obesity
induces PAI-1 in adipose tissue and glomerular cells where it is an independent risk factor for
renal damage through its effects to decrease protease-dependent matrix degradation and
cellular migration.[45] In a podocyte injury-associated glomerulosclerosis model,
renoprotection conferred by PPAR-γ agonist is achieved, in part, through decreased PAI-1.
[46] Interestingly, preliminary studies suggest PAI-1 also modulates podocyte injury. Thus,
renal ablation in PAI-1 deficient mice caused less proteinuria, glomerular sclerosis, podocyte
damage/loss. These in vivo findings were paralleled by decreased angiotensin-induced
apoptosis in cultured PAI-1 deficient podocytes compared with PAI-1 intact cells. These results
are of interest because of the highly differentiated nature of podocytes, which once lost, are
not replenished and thought to promote intraglomerular injuries that lead to glomerular
sclerosis. (Unpublished data.)
Melanocortin
The central nervous melanocortin system plays a pivotal role in regulating body weight and
energy homeostasis.[47] Melanocortin 4 receptor (MC4-R) has been identified as the cause of
rare forms of monogenic obesity and heterozygous mutations in the MC4-R gene account for
about 6% of early onset or severe adult obesity.[48] Novel non-selective melanocortin receptor
agonists improve obesity, hyperinsulinemia and fatty liver disease in obese C57BL/6 mice.
[49] Recently, the effects of melanocortin-4 receptor in obesity-associated renal injury were
studied in MC4R−/− mice.[50] Although MC4R−/− mice exhibited many characteristic of the
metabolic syndrome, including increased weight, hyperinsulinemia, and hyperleptinemia, they
were not hypertensive. Although treatment with L-NAME caused a similar increase in systemic
blood pressure in both MC4R−/− and age-matched wild type mice, the MC4R−/− developed
more renal injury including greater elevation in urine albumin, renal TGF-β content and renal
macrophage infiltration. These results emphasize that hypertension is an important risk factor
for obesity related kidney injury in MC4R−/− mice.
Metabolic/adipose factors
Obesity causes lipid disturbances that may directly contribute to renal damage. Young C57BL/
6 mice fed a HFD became heavier, developed hyperglycemia, hyperinsulinemia, elevated
triglycerides and cholesterol and lower circulating adiponectin. They became proteinuric and
had morphological abnormalities including, glomerulomegaly, expanded mesangial matrix,
GBM thickening and podocyte effacement.[51] A dramatic increase in mesangial area was also
observed in young obese Zucker rats fed a HFD, an abnormality which normalized by treatment
with rosuvastatin.[52] Lipid moieties can directly injure renal parenchymal cells. Human
mesangial cells exposed to LDL, oxidized LDL, and glycated LDL at concentrations
approximating those in circulation dramatically increased synthesis of mesangial matrix
components, fibronectin and laminin.[53] The lipid moieties also promoted mesangial
production of macrophage migration inhibitory factor, and increased expression/release of
inflammatory activators, CD40 and IL-6.[53] Treatment of hyperlipidemic mice with anti-IL-6
monoclonal antibody ameliorated lipid-induced renal toxicity, including glomerular lipid
accumulation, mesangial cell proliferation and matrix accumulation, resulting in normalization
of proteinuria.[54] Lipids also directly damage podocytes. [14] Oxidized LDL causes
redistribution and loss of nephrin as well as podocyte apoptosis by decreasing phosphorylation
of Akt, a prominent pathway for cell survival.[55,56] Additional podocyte metabolic pathways
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may be altered by lipids. Thus, podocytes cultured with the saturated fatty acid, palmitate,
increased ceramide production resulting in blockade of insulin-stimulated glucose uptake.
[57] Fatty acid-induced insulin resistance in podocytes appears to represent a novel nexus
where lipid abnormalities and altered glucose metabolism may interact directly to foster
nephropathy.
Sterol regulatory element binding protein-1 (SREBP-1) appears to play a critical role in the
renal lipid accumulation, subsequent inflammatory/fibrotic response, and resultant injury.
[58] [59] Thus, renal effects of a HFD were not seen in SREBP-1c −/− mutant mice, while
SREBP-1a transgenic mice had increased glomerular lipid accumulation, markers of
glomerulosclerosis as well as increased albuminuria. Ameliorating effects were recently
observed for farnesoid X receptor.[60] Lending credence to these data for human disease are
observations that glomerular expression of SREBP-1 is up-regulated two fold in glomeruli
from patients with obesity related glomerulopathy.[61]
Adipose tissue produces a number of bioactive substances. Leptin was originally identified as
a murine obesity gene product abundantly produced by adipose tissue and regulates the
hypothalamic-pituitary axis involved in food intake, energy expenditure and intracellular lipid
homeostasis. Circulating levels of leptin parallel fat stores and absence of leptin or mutation
in the leptin receptor gene causes massive hyperphagia in animals and humans. Despite severe
obesity, these mutations are not accompanied by renal dysfunction. Contrasting adiposeoriginating
cytokines which are elevated, adiponectin levels are depressed in obesity. Low
adiponectin levels have been associated with inflammation, atherosclerosis, insulin resistance,
and augmentation of blood pressure.[62] Experimental and clinical hypoadiponectinemia is
associated with endothelial cell dysfunction, impaired endothelium-dependent vasodilation,
disinhibition of leukocyte-endothelium adhesion, and activation of RAAS. Adiponectin also
supports normal function of the podocyte[63] and hypoadiponectinemia may impair the pivotal
role of podocytes in maintaining an intact glomerular sieving barrier and promote
intraglomerular injuries that lead to glomerular sclerosis. Thus, adiponectin null mutant mice
have an exaggerated response to renal injury including glomerulomegaly, glomerular collagen
deposition, podocyte foot process effacement, increased TGF-β, and albuminuria.[64]
Adiponectin treatment normalizes podocyte effacement and albuminuria. At least in part,
adiponectin’s benefit may be through reduction in oxidant stress.[63] [65] Conversely,
adiponectin deficiency leads to augmentation of NADPH oxidase and increase in urinary
reactive oxygen species. It is of interest that obese African-Americans show a strong negative
correlation between plasma adiponectin levels and albuminuria.[63] Importantly, adiponectin
level can increase even with modest weight loss. Only 1 month after bariatric surgery, obese
patients had a significant increase in adiponectin.[66]
Adiposity-driven proinflammatory cytokines
Fat distribution, specifically visceral adiposity, is a key determinant of renal dysfunction, even
in normal weight individuals.[67] The role of the visceral fat relates not only to secretion of
bioactive substances, but also to promote a low grade chronic inflammatory state. Visceral fat
is infiltrated by macrophages which constitute an important source of pro-inflammatory
mediators. Macrophages also have a reciprocal relationship with adipocytes. For example, fatty
acids released by adipocytes stimulate TNF-α release by macrophages which, in turn, can
stimulate production of IL-6 by fat cells further amplifying the inflammatory response in
adipose tissue as well as the kidney.[68] TNF-α is a key mediator of progressive renal fibrosis.
Gene expression profiles in glomeruli obtained from renal biopsy samples of patients with
ORG showed increased TNF-α and its receptors, suggesting TNF-α’s role in development of
ORG.[61] Interleukin-6 is secreted by adipose tissue and circulating levels increase with
obesity, with as much as 30% derived from adipose tissue.[69] Glomeruli from patients with
Hunley et al. Page 5
Curr Opin Nephrol Hypertens. Author manuscript; available in PMC 2011 May 1.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
ORG show increased expression of IL-6 signal transducer, pointing to the possibility of IL-6
pathogenicity in glomeruli.[61] Many of the bioactive substances produced by macrophages
also inhibit preadipocyte differentiation, further expanding a population of large,
dysfunctional, insulin-resistant adipocytes that fuel the vicious cycle between obesity and renal
injury.
Adiposity-driven macrophage infiltration and phenotypic switch
Obesity-related macrophage infiltration of adipose tissue is believed to be key in inflammation
and insulin resistance.[70] [71] Importantly, depending on the local microenvironment and
stage of tissue injury, macrophages display heterogeneity in functions.[72] [73] [74] Thus, M1
or “classically activated” macrophages are induced by classical immune pathways and function
to enhance proinflammatory cytokine production (IL-1β, TNF-α, IL-6). By contrast, M2 or
“alternatively activated” macrophages function in the resolution of inflammation and tissue
repair through synthesis of anti-inflammatory cytokines IL-10 and IL-1 decoy receptor and
possess high endocytic clearance capacities.[75] [74] [73] Obesity induces macrophage
phenotypic switch in adipose tissue,[76] shifting from M2 phenotype predominating in lean
rodents to a robust increase in proinflammatory M1 macrophage population in obese animals.
[77] [78]
Experimental approaches to inhibit proinflammatory macrophages have been successful in
reducing kidney injury.[79] [80] [81] The possibility that phenotypic alteration of macrophages
modulate obesity-associated CKD has recently been evaluated. Using AT1a receptor knockout
mice (AT1aKO) and a high-fat diet-induced obesity model, we recently found that HFD feeding
augmented renal injury, including mesangial expansion and tubular vacuolization in AT1aKO
(submitted for publication). There was significantly greater macrophage infiltration in visceral
adipose tissue and kidney of obese AT1aKO. Kidney M1 macrophage activation was markedly
induced while kidney M2 activation was reduced by half in obese AT1aKO. Further, M1, but
not M2, activation in peritoneal macrophages was enhanced in obese AT1aKO. These data
reveal a new role of macrophage AT1 receptor in mediating macrophage polarization and
suggest that AT1a deficiency reduces the population of potentially beneficial M2 macrophages
and promotes obesity-related renal damage.
In conclusion, new evidence indicates that in addition to promoting diabetes, hypertension,
and cardiovascular disease; obesity per se, causes pathophysiologic disturbances that adversely
affect kidney function and structure. These abnormalities are remediable through weight
reduction and inhibition of RAS, an approach that will likely be supplanted with interventions
that directly target adipocyte-associated cytokines and inflammatory factors.

Obesity is the next major epidemiologic challenge facing

today’s doctors, with the annual allocation of healthcare resources
for the disease and related comorbidities projected to exceed $150
billion in the United States. The incidence of obesity has risen in the
United States over the past 30 years; 60% of adults are currently either
obese or overweight. Obesity is associated with a higher incidence of
a number of diseases, including diabetes, cardiovascular disease, and
cancer. Consumption of fast food, trans fatty acids (TFAs), and fructose—
combined with increasing portion sizes and decreased physical
activity—has been implicated as a potential contributing factor in the
obesity crisis. The use of body mass index (BMI) alone is of limited
utility for predicting adverse cardiovascular outcomes, but the utility
of this measure may be strengthened when combined with waist
circumference and other anthropomorphic measurements. Certain
public health initiatives have helped to identify and reduce some of
the factors contributing to obesity. In New York City and Denmark,
for example, such initiatives have succeeded in passing legislation to
reduce or remove TFAs from residents’ diets. The obesity epidemic
will likely change practice for gastroenterologists, as shifts will be seen
in the incidence of obesity-related gastrointestinal disorders, disease
severity, and the nature of comorbidities. The experience gained
with previous epidemiologic problems such as smoking should help
involved parties to expand needed health initiatives and increase the
likelihood of preventing future generations from suffering the consequences
of obesity.

BACO LO YANG KO HAAAA YOOOO

1. The Medical Risks of Obesity

Xavier Pi-Sunyer, MD1
1Division of Endocrinology, Diabetes and Nutrition, St. Luke's-Roosevelt Hospital Center, Columbia
University, New York, NY
Waist Circumference as Compared with Body-Mass
Index
in Predicting Mortality from Specific Causes
Michael F. Leitzmann1,2*, Steven C. Moore1, Annemarie Koster3,4, Tamara B. Harris3, Yikyung Park1,
1. Albert Hollenbeck5, Arthur Schatzkin1

The effect of obesity on chronic respiratory diseases:

pathophysiology and therapeutic strategies
Magali Poulain, Mariève Doucet, Geneviève C. Major, Vicky Drapeau, Frédéric Sériès,
Louis-Philippe Boulet, Angelo Tremblay, François Maltais

Pulmonary Physiology and Pathophysiology in Obesity

Obesity and lung inflammation
Peter Mancuso