Nutrients 2013, 5, 2019-2027; doi:10.

3390/nu5062019
OPEN ACCESS

nutrients
ISSN 2072-6643
www.mdpi.com/journal/nutrients
Review

Body Fat Distribution and Insulin Resistance

Pavankumar Patel * and Nicola Abate

Division of Endocrinology, Department of Internal Medicine, University of Texas Medical Branch,

301 University Blvd, Galveston, TX 77555, USA; E-Mail: [email protected]

* Author to whom correspondence should be addressed; E-Mail: [email protected];

Tel.: +1-409-772-6314; Fax: +1-409-772-8709.

Received: 8 April 2013; in revised form: 23 May 2013 / Accepted: 24 May 2013 /
Published: 5 June 2013

Abstract: The burden of obesity has increased globally over the last few decades and
its association with insulin resistance and related cardio-metabolic problems have
adversely affected our ability to reduce population morbidity and mortality. Traditionally,
adipose tissue in the visceral fat depot has been considered a major culprit in the
development of insulin resistance. However, there is a growing body of evidence supporting
the role of subcutaneous truncal/abdominal adipose tissue in the development of insulin
resistance. There are significant differences in the functional characteristics of subcutaneous
abdominal/truncal vs. intraabdominal vs. gluteo-femoral fat depots. More recently, mounting
evidence has been supporting the role of adipose tissue function in the development of
metabolic complications independent of adipose tissue volume or distribution. Decreased
capacity for adipocyte differentiation and angiogenesis along with adipocyte hypertrophy
can trigger a vicious cycle of inflammation leading to subcutaneous adipose tissue
dysfunction and ectopic fat deposition. Therapeutic lifestyle change continues to be the most
important intervention in clinical practice to improve adipose tissue function and avoid
development of insulin resistance and related cardio-metabolic complications.

Keywords: adipose tissue; adipose tissue distribution; adipose tissue dysfunction; adipose
tissue inflammation; body fat distribution; insulin resistance
Nutrients 2013, 5 2020

1. Introduction

The increasing global burden of obesity has become a major public health problem. The most recent
(2010) analysis by the International Association for the Study of Obesity (IASO) and International
Obesity Taskforce (IOTF) reports that the number of adults globally who are overweight or obese is one
billion and 475 million, respectively [1]. IASO/IOTF also estimate that the number of children worldwide
who are either overweight or obese is 200 million [1]. Similar trends have been noticed in the United
States. The National Health and Nutrition Examination Survey (NHANES) estimates that 33.8% of
adults (age 20 years or more) and 16.8% of children and adolescents (age 2–19 years) are obese [2,3].
Obesity is associated with a variety of medical conditions including cardiovascular disease (CVD), diabetes
mellitus, hypertension, dyslipidemia, nonalcoholic fatty liver disease, cancers, and sleep apnea [4].
Insulin resistance is an underlying key pathophysiologic process in the development of cardio-metabolic
disorders among obese individuals. Insulin resistance leads to development of an atherogenic
dyslipidemic profile, and prothrombotic and proinflammatory states. Dyslipidemia in insulin resistant
individuals is characterized by elevated triglycerides, apolipoprotein B, small dense low density
lipoprotein (LDL) particles, and reduced high density lipoprotein (HDL) concentration and smaller
HDL particle size. Insulin resistance also leads to elevated blood pressure and glucose intolerance,
which in the presence of genetic and environmental factors, can progress to hypertension and type 2
diabetes mellitus [5].
The relationship between obesity and cardio-metabolic disorders is more complex than it appears.
Many epidemiologic and clinical studies have suggested that 10%–40% of obese individuals are
metabolically healthy. The metabolically healthy obese (MHO) phenotype exhibits higher insulin
sensitivity, absence of hypertension, and favorable lipid, inflammation, hormonal and liver enzyme
profile [6]. Vice versa, metabolic abnormalities can occur in normal weight individuals. This
metabolically obese but normal weight phenotype is characterized by not being obese on the basis of
height and weight but with hyperinsulinemia, insulin resistance and increased risk for type 2 diabetes,
hypertriglyceridemia and atherosclerosis [7]. One explanation for metabolically obese normal weight
profile is variability in the body fat content for any given Body Mass Index (BMI). Recent studies
performed within the NHANES III population have revealed that about 10% of the US population is
estimated to have a normal BMI but increased body fat content [8,9].
However, another major contributing factor in variability in body fat-related metabolic complications
is fat distribution in various adipose tissue areas. Adipose tissue can be divided into truncal region or
peripheral region. Truncal adipose tissue includes subcutaneous fat in thoracic and abdominal region and
also fat in intrathoracic and intraabdominal regions. Peripheral adipose tissue includes subcutaneous
depots in upper and lower extremities [10].
The association between regional fat distribution and cardio-metabolic complications was first
suggested by Vague in 1947. Vague described two patterns of adipose tissue distribution—android
(upper body) and gynoid (lower body)—and suggested that android obesity was associated with
diabetes, coronary artery disease, gout and uric acid renal stones [10]. Later on in 1980s, Lapidus L et al.
reported that Waist to Hip circumference ratio, compared to other anthropometric measures, was
positively associated with a 12-year incidence of myocardial infarction, angina pectoris, stroke, and
death [11]. Subsequently, many clinical studies have established association between increased Waist to
Nutrients 2013, 5 2021

Hip circumference ratio and cardiovascular diseases. The INTERHEART study examined the effect of
different measures of obesity on the risk of myocardial infarction in multiple populations from
52 countries across the world [12]. Study investigators found that Waist to Hip ratio, and the waist and
the hip circumferences, were highly associated with risk of acute myocardial infarction independent of
other risk factors. The European Prospective Investigation into Cancer and Nutrition in Norfolk Cohort
(EPIC) study prospectively examined the relationship between body fat distribution and risk of coronary
heart disease [13]. After 9.1 years of follow up, investigators reported that waist circumference was a
significant estimate for coronary artery disease events. In the Atherosclerosis Risk in Communities
(ARIC) study, Waist to Hip ratio was associated with increased risk for non-lacunar and cardio-embolic
stroke [14]. Waist to Hip ratio, being a simple index of body fat distribution, when elevated crudely
indicates increased proportion of abdominal adipose tissue. In fact, over the last few decades evidence
has accumulated to support the concept of abdominal adipose tissue as a determinant of
insulin resistance.
To be more precise, many investigators have reported that intraabdominal (visceral) adipose tissue is
a major contributor to metabolic risk [15–17], whereas some investigators have suggested that subcutaneous
adipose tissue may have a protective role [18]. Intraabdominal adipose tissue has increased metabolic
(both lipogenesis and lipolysis) activity. According to the portal vein hypothesis, free fatty acids, as a
product of lipolysis, directly enter the liver via portal vein and lead to increased lipid synthesis,
gluconeogenesis, and insulin resistance. This can result in hyperlipidemia, glucose intolerance,
hypertension and ultimately atherosclerosis [15]. Excess free fatty acids can inhibit skeletal muscle
glucose uptake and lead to peripheral insulin resistance [10].
However, if visceral fat was a major contributor to metabolic risk, visceral adipose tissue should be
the major source of systemic free fatty acid flux. Only a small portion of total body fat, 15%–18% in men
and 7%–8% in women, is located in the abdominal cavity [19]. Visceral fat contributes to only 15% of
the total systemic free fatty acids whereas majority of free fatty acid is contributed by nonsplanchnic
adipose tissue [10,20]. This observation raises the doubt over notion that visceral adipose tissue is a sole
determinant of peripheral insulin sensitivity.
We have examined the relationships between generalized and regional adiposity and insulin sensitivity in
a group of nondiabetic men with varying degree of obesity [21]. We concluded that subcutaneous truncal
fat plays a major role in obesity related insulin resistance in comparison to visceral or retroperitoneal fat.
Subsequently, we examined a similar relationship among men with noninsulin dependent diabetes
mellitus (NIDDM) and found that NIDDM men had a fat distribution pattern that favors truncal
subcutaneous depot than peripheral subcutaneous or intraperitoneal fat depot [22]. Truncal subcutaneous
fat content had a stronger correlation with insulin sensitivity than visceral fat among NIDDM men.
Goodpaster, B.H. et al. has also demonstrated a stronger relationship between subcutaneous abdominal
fat and insulin sensitivity [23]. Cross sectional analyses of data from the Amsterdam Growth and Health
Longitudinal Study by Ferreira I et al. revealed that high subcutaneous trunk fat was associated with
arterial stiffness [24]. The stronger relationship between subcutaneous adipose tissue and insulin
resistance can be related to relatively larger subcutaneous adipose tissue mass. Subcutaneous abdominal
fat mass is two times more than the intraperitoneal fat mass. However, if we consider total subcutaneous
truncal fat mass, it is approximately 4–5 times more than the intraperitoneal fat mass [21,22,25].
Similarly in women, subcutaneous abdominal fat area at a L4–L5 level is approximately five times more
Nutrients 2013, 5 2022

than the visceral fat area at the same level [25–27]. We can postulate that subcutaneous truncal adipose
tissue, merely because of its larger volume, can be a major contributor of systemic free fatty acid flux
and therefore, insulin resistance.
Inflammation in adipose tissue, as suggested by the presence of macrophage in the form of crown-like
structures (CLS), has been identified as a mediator of systemic insulin resistance. Apovian, C.M. et al.
examined relationships between adipose tissue macrophage infiltration and insulin resistance and
vascular endothelial dysfunction in obese individuals [28]. Inflamed subcutaneous adipose tissue
phenotype, characterized by the presence of macrophage in crown-like structures, was associated with
systemic hyperinsulinemia, insulin resistance, impaired endothelium-dependent flow-mediated
vasodilatation and elevated plasma hs-CRP levels. Other investigators have also reported similar
association between macrophage infiltration of subcutaneous adipose tissue and insulin resistance and
low grade systemic inflammation [29,30]. Lê, K.A. et al. examined the influence of subcutaneous
adipose tissue (SAT) inflammation on hepatic fat fraction, visceral adipose tissue, insulin sensitivity,
beta cell function and SAT gene expression [30]. Subcutaneous adipose tissue inflammation, independent
of total adiposity, was associated with partitioning of fat towards the visceral adipose tissue and liver and
altered beta cell function. In addition, several genes belonging to nuclear factor-κB stress pathway were
up regulated suggesting stimulation of inflammatory mediators.
Attempts have been made to identify triggers for adipose tissue inflammation and subsequent
development of insulin resistance. In the presence of increased caloric intake, adipocytes in subcutaneous
adipose tissue with decreased adipogenic potential undergo hypertrophy. This results in local hypoxic
environment and macrophage infiltration. van Tienen, F.H. et al. reported that preadipocytes of type 2
diabetes subjects display decreased expression of genes involved in differentiation suggestive of
decreased adipogenesis [31]. Goedecke, J.H. et al. reported association between decreased insulin
sensitivity and decreased expression of adipogenic and lipogenic genes in subcutaneous adipose tissue
of obese black South African women [32]. Lundgren, M. et al. examined the relationship between fat
cell size and insulin sensitivity [33]. Enlarged adipocytes were found in patients with type 2 diabetes and
prediabetic individuals and were an independent marker of insulin resistance in prediabetic
subcutaneous adipose tissue. We have reported that migrant South Asians, compared to Caucasians,
have excess insulin resistance without increase in the intraperitoneal fat mass. They had increased
adipocyte size in the subcutaneous abdominal adipose tissue and elevated plasma hs-CRP suggestive of
low grade systemic inflammation [34,35]. In addition to decreased adipogenesis, subcutaneous adipose
tissue exhibits decreased angiogenic capacity. Gealekman, O. et al. reported that angiogenic capacity of
subcutaneous abdominal adipose tissue decreased with increasing body mass index but it did not change
in visceral adipose tissue [36]. Decrease in angiogenic capacity correlated with insulin resistance,
which suggests that impairment in subcutaneous adipose tissue angiogenesis may contribute to
metabolic complications.
In contrast to abdominal subcutaneous adipose tissue, larger subcutaneous thigh fat has a protective
effect. The Health, Aging, and Body Composition Study reported that large subcutaneous thigh fat was
independently associated with more favorable glucose (in men) and lipid profile (in both genders) [37].
The Australian Diabetes, Obesity and Lifestyle Study, a large population based study, examined
association between waist and hip circumferences to components of metabolic syndrome [38]. After
adjustment for age, BMI and waist, a larger hip circumference was associated with a lower prevalence of
Nutrients 2013, 5 2023

undiagnosed diabetes and dyslipidemia. Association with undiagnosed hypertension was weaker. Vice
versa, low subcutaneous thigh fat was associated with the adverse metabolic profile. The Quebec family
study examined effects of waist and hip circumferences on cardiovascular risk factors [39]. A narrow hip
circumference (adjusted for age, BMI, and waist circumference) was associated with low
HDL-cholesterol and high glucose concentrations in men and high triacylglycerol and insulin
concentrations in men and women.
Finally, it is worth summarizing the role of subcutaneous adipose tissue characteristics in the
development of insulin resistance. It can be envisioned that persisting excess in caloric intake is usually
met by an increase in fat deposition, predominantly occurring in the subcutaneous adipocytes. Truncal
vs. peripheral deposition could be determined by genetic and environmental factors, currently a matter of
intense investigation. This buffering function of subcutaneous adipose tissue can be envisioned as
continuing until a tipping point is reached. This happens when decreased adipogenesis and decreased
angiogenesis, along with adipocyte hypertrophy, sets up an inflammatory reaction characterized by
activation of nuclear factor-KB pathway. The resultant effects are: down regulation of cellular insulin
signaling, recruitment of additional macrophages through monocyte chemoattractant protein 1,
propagation of inflammation by interleukins and tumor necrosis factor alpha, and tissue matrix
remodeling through matrix metalloproteinase-9 [30]. These inflammatory mediators, as well as yet not
well-defined metabolic pathways, may limit the recruitment and maturation of new adipocytes.
Subcutaneous adipose tissue, which is now dysfunctional and not able to expand, cannot continue to
serve as an energy buffer. At this point, positive energy balance results in a spillover of fatty acids and
triglycerides in ectopic tissues. Fat deposition in skeletal muscle results in decreased activity of glucose
transporter (GLUT 4) and decreased glucose uptake. Hepatic steatosis results in hepatic insulin
resistance which leads to decreased glucose uptake and increased glucose production. Free fatty acid
accumulation in the heart can result in diastolic dysfunction [40]. It is possible that, depending on the
environmental and genetic factors, “tipping point” may be reached at different levels of adiposity,
including in a non-obese range, and it may not be reached at all even with morbid obesity. It is possible
that increased fat in subcutaneous depot relative to visceral depot may not be accompanied by an
increase in insulin resistance since “tipping point” is not reached.

2. Conclusion

There is enough evidence in the existing literature for association between increased adiposity and
insulin resistance. Attempts have been made to identify one particular adipose tissue depot as a sole
contributor to insulin resistance and cardio-metabolic complications. Many investigators have suggested
that visceral adipose tissue is a major contributor to insulin resistance. Our previous studies, in
concordance with those of other investigators, suggest that subcutaneous truncal adipose tissue has
significant impact on the development of insulin resistance. In fact, subcutaneous adipose tissue appears
to have a major function as a metabolic buffer. In the presence of positive caloric balance, subcutaneous
adipose tissue eventually becomes dysfunctional due to adipocyte hypertrophy, decreased adipogenesis
and angiogenesis. At this point, buffering function is lost and excess free fatty acids spill over into
ectopic tissues, resulting in tissue specific consequences. Therapeutic lifestyle change, including
physical activity, weight loss and healthy diet continue to be the most important interventions to restore
Nutrients 2013, 5 2024

the buffering capacity of subcutaneous adipose tissue. PPAR-gamma ligands have also been shown to
serve the same purpose and decrease ectopic fat deposition. Future research will have to be focused on
effective and safe therapeutic targets to accomplish the proven metabolic benefit of amelioration in
adipose tissue function and ultimately allow more effective interventions to improve morbidity and
mortality among metabolically obese patients.

Conflict of Interest

The authors declare no conflict of interest.

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