Inflammation and Cell Signaling 2014;1: e154.

http://www.smartscitech.com/index.php/ics

RESEARCH
REVIEW HIGHLIGHT

Adiponectin and Alzheimer's disease: Is there a link?

Zhongxiao Wan, Jonathan P. Little
School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, British Columbia, V1V 1V7
Canada
Correspondence: Jonathan P. Little
E-mail: [email protected]
Received: April 14, 2014
Published online: June 14, 2014

Obesity is a recently established risk factor for Alzheimers disease (AD) and dementia. The mechanisms linking
obesity to AD have not been firmly established and therefore no evidence-based hypotheses exist for designing
preventative or therapeutic interventions. Adiponectin is the most abundant adipokine in the circulation and its levels
are substantially reduced in obesity. In peripheral tissues, adiponectin exerts a wide range of beneficial physiological
actions, including anti-diabetic, anti-inflammatory, anti-atherosclerotic and cardioprotective effects. Several different
lines of evidence indicate that adiponectin exerts effects on the brain, but data is still conflicting. Recently work from
our laboratory confirmed the expression of adipoR1 and adipoR2 in primary human astrocytes isolated from adult
brain samples and we found that globular adiponectin induced astrocyte inflammation. Due to the prominent role of
brain inflammation in AD, astrocyte inflammation induced by globular adiponectin could be involved in AD-related
pathology. In this brief review, we summarized the evidence connecting obesity and AD, with a specific focus on the
potential involvement of adiponectin. We also suggest approaches for further exploring adiponectin's effects in AD
pathogenesis. Elucidating the role of adiponectin in AD-related pathology will hold promise for identifying potential
therapeutics that could promote positive effects of adiponectin for the prevention and/or treatment of AD and
dementia in the context of obesity.
Keywords: adipokines; astrocytes; dementia; obesity; high fat diet; neuroinflammation
Inflammation & Cell Signaling 2014; 1: e154. doi: 10.14800/ics.154; 2014 by Zhongxiao Wan, et al.

satisfying therapy nor a preventative cure is available for

AD. This is largely because our knowledge of the
complex biology of AD is incomplete, highlighting the
importance of exploring and understanding new mechanisms underlying AD progression.

1. Introduction
Alzheimer's disease (AD) is characterized by
progressive cognitive decline, loss of memory, and
dementia, and is the most common neurodegenerative
disease in humans. The pathological hallmarks of the
disease are neurofibrillary tangles (NFTs) comprised of
hyperphosphorylated tau[1] and senile plaques comprised
of amyloid beta (A)[2], which result in neuronal death
and dysfunction. A significant inflammatory component
is also present in brains of individuals with AD,
consisting of activated microglia and astrocytes and an
increase in levels of brain cytokines[3-4].The disclosure of
AD presents a great challenge because it not only affects
patients quality of life but also has significant impact on
family members and caregivers. At present, neither a

2. Obesity and increased risk of AD

The most significant risk factor for AD is aging but
mounting evidence now suggest that obesity represents
an independent risk factor for AD and related
dementias[5-7]. Research linking obesity to AD can be
summarized as follows: 1) Longitudinal studies report
that overweight, obesity, and/or increased abdominal
adiposity in mid-life result in ~1.5 to 3-fold greater risk

Zhongxiao Wan, et al.

Adiponectin as a link between obesity and AD

of developing AD, dementia or cognitive impairment

later in life[5-6; 8-10]; 2) Many consequences of
obesity-including impaired glucose tolerance, type 2
diabetes (T2DM), and cardiovascular disease-are also
risk factors for AD[11-15]. Increased risk of AD in obesity
and T2DM is separate from vascular dementia and
appears to persist after adjustment for cardiovascular risk
factors such as stroke, hypertension, and cerebrovascular
disease, suggesting an independent role for obesityrelated metabolic dysfunction; 3) High-fat feeding, which
is used to model obesity, results in impaired cognitive
function in rodents[16-17] and humans[18], as well as
increased astrogliosis[19-21], and microglial activation[17;
19-21]
in rodent brains; 4) A recent review using
population attributable risk scores estimated that 7% of
all AD cases in the USA can be attributed to midlife
obesity[22]. Despite this mounting evidence supporting the
association between obesity and increased risk of AD, the
mechanistic links between obesity and AD brain
pathology remain incompletely understood.

adiponectin enters the brain fluid from the circulation,

and the trimer and hexamer forms of adiponectin can be
detected in the cerebrospinal fluid[35-38]. Lee et al.[39]
reported that adiponectin knockout (KO) mice have
enhanced kainic acid-induced seizure severity, but only
when animals are rendered obese through high-fat
feeding. This provided the first evidence suggesting that
adiponectin could link obesity-related metabolic
dysfunction to greater risk of neurodegeneration.
Substantial associative evidence also supports a
neuroprotective effect of adiponectin, including: 1)
Clinical and animal studies report that thiazolidinediones
(TZDs) and omega-n-3 poly- unsaturated fatty acids
(PUFAs) have benefits on cognitive impairment
associated with dementia and AD[40-42]. An increase in
plasma adiponectin is one of the most notable and
common responses to TZDs treatment and n-3 PUFAs
supplementation[41-42]. Thus, adiponectin might play a
role in TZDs and n-3 PUFAs beneficial effects on the
brain. 2) Insulin resistance is another significant risk
factor for AD[5; 43]. Longitudinal studies show that insulin
resistance is associated with increased risk of AD[44-45],
increased amyloid A plaques and NFTs[43] and
hippocampal atrophy[46]. Adiponectin is a well-known
insulin sensitizer[27-28]. By enhancing insulin sensitivity,
adiponectin might reduce brain pathology and AD risk.
Furthermore, at the cellular level, Chan et al.[33] reported
that high concentrations of adiponectin (10 g/ml) were
protective against amyloid beta induced neurotoxicity in
Sw-APP transfected SH-SY5Y cells exposed to oxidative
stress conditions, further supporting adiponectin might be
protective against AD.

3. Adiponectin: a potential mechanistic link between

obesity and AD?
3.1 Evidence gleaned from adiponectin action in
peripheral tissues
It is now well-accepted that adipose tissue is an active
endocrine organ that secretes a host of hormone-like
substances termed adipokines[23]. Adipose tissue
contains adipocytes, preadipocytes, endothelial cells, and
various immune cells and thus adipokines may originate
from any one of these diverse cell types. Adiponectin, the
most abundant adipokine in circulation, is thought to be
secreted almost exclusively by adipocytes[24]. Several
experimental and clinical studies have shown that
adiponectin is inversely related with adiposity, resulting
in lower circulating levels of adiponectin in obesity[25-26].
In peripheral tissues, adiponectin improves insulin
sensitivity[27-28] and vascular function[29], and has
anti-atherogenic, anti-inflammatory actions[30] and
cardioprotective effects[31]. Thus, reduced adiponectin in
obesity could indirectly influence AD risk through
modulation of several interrelated systemic factors.
However, emerging, yet currently incomplete, evidence
suggests that adiponectin may impact AD risk through
direct effects in the brain.

3.3 Potential detrimental effects ofadiponectin in the

CNS
In contrast to the above mentioned benefits of
adiponectin on AD risk there is also evidence supporting
a detrimental effect of adiponectin with regards to
neurodegeneration. The Framingham Heart Study
showed that individuals with higher levels of adiponectin
had increased risk of future dementia[47]. Une et al. [48]
have also reported elevated cerebrospinal fluid
adiponectin in older adults with mild cognitive
impairment compared to healthy age-matched
individuals, suggesting that elevated CNS adiponectin
tracks AD risk. A pathogenic role for adiponectin has
also been described in ischemic stroke, where adiponectin
receptor 1 (adipoR1) expression is increased and globular
adiponectin (gAd) enhances neuronal cell death in
response to glucose and oxygen deprivation[49]. Recently,
work from our laboratory confirmed the expression of
adipoR1 and adipoR2 in primary human astrocytes

3.2 Potential beneficial effects of adiponectin in the

central nervous system (CNS)
Adiponectin receptors are widely distributed in the
CNS[32-34]. Recent studies show that circulating

Zhongxiao Wan, et al.

Adiponectin as a link between obesity and AD

monomers by neutrophil elastase[58]. Different isoforms

of adiponectin have been shown to play distinct
biological roles in peripheral tissues[59-60]. Our recently
published data suggest that globular adiponectin (1g/ml)
induces a pro-inflammatory state in human astrocytic
U373 MG cell line[34], which is in consistent with the
findings about globular adiponectin in peripheral
tissues[61-62]. This data suggesting a link between globular
adiponectin and AD-related brain pathology (i.e.,
inflammation) is consistent with studies reporting that
globular adiponectin enhances neuronal death under
hypoxic conditions[49]. The roles played by other forms of
adiponectin in neuroinflammation and neurodegeneration
require further exploration. Future cellular research is
also needed to study potential interactions between the
different forms of adiponectin and other established
signaling molecules in AD-related pathology.

isolated from adult brain samples and we found that gAd

induced
astrocyte
inflammation[34].
Based
on
pharmacological inhibitor experiments, the induction of
inflammatory cytokine production in astrocytes appeared
mediated by several classical inflammatory pathways,
including nuclear factor kappa B (NFB), p38
mitogen-activated protein kinase (MAPK), c-Jun
N-terminal kinase (JNK), phosphatidylinositide 3-kinase
(PI3K), and particularly extracellular signal-related
kinase (ERK) 1/2[34]. Thus, augmented brain inflammation may be a potential cellular mechanism linking
adiponectin with the previously described neurodegenerative consequences[34]. Further studies are warranted
to examine the impact of adiponectin on brain function in
neurodegenerative disorders including AD. One
physiological complication in studies of adiponectin and
dementia is the association with energy balance.
Adiponectin tends to increase in conditions of negative
energy balance (i.e., weight loss) yet weight loss has been
shown to be a significant predictor of impending
dementia[50-51]. Therefore, in studies showing an
association between increased adiponectin and cognitive
impairment[47,48] it is possible that negative energy
balance was a confounding factor.

3) Adipose tissue conditioned media (ATCM): a model

of adipose-brain crosstalk?
Adiponectin is one of the most abundant proteins in
serum, circulating in the g/ml range. The physiological
levels of adiponectin in human cerebrospinal fluid are
reported to be ~1000-fold less than in serum[63]. It is of
importance to explore how adiponectin, at physiological
levels, exert its action in the CNS, as well as determining
the function of adiponectin in combination with other
adipokines. In this regard, human adipose tissue
conditioned media provides a unique way to explore
potential adipose-brain crosstalk. Adipose tissue organ
culture (ATOC) is a well-recognized technique to study
adipose tissue function that maintains the complex
interplay of cells that is representative of normal
physiology [64]. ATOC is a relatively easy technique and
cultures can be prepared from surgical or biopsy
samples[64] from different adipose tissue depots. ATCM
can be stored at -80C and further utilized for transferring
to different cell lines (such as neuronal or glial cell
cultures). This technique allows the paracrine and/or
autocrine interactions between adipocytes and other cell
types in adipose tissue to remain intact and is arguably
more representative of what is seen in vivo compared to
isolated adipocyte preparations. Thus, altered adipokine
secretion from subjects with different metabolic
status(such as lean vs. obese, and non-T2DM vs. T2DM)
can be prepared and ATCM can be used to treat brain cell
cultures to study how physiological combinations of
adipokines impact mechanisms of neurodegeneration.
Because adipose tissue remains buoyant and floats during
ATOC procedures, direct co-culture of adipose with
adherent brain cell lines can also be performed with, or
without, the use of tissue culture inserts. These
techniques will be potentially useful for exploring
whether altered adipose tissue secreted factors (especially

3.4 Potential approaches to further explore the action

of adiponectin in the pathogenesis of AD
1) Adiponectin knockout (KO) mice
Multiple strains of adiponectin KO mice have been
created in different laboratories[52-55]. Although
phenotypes are somewhat variable, generally adiponectin
KO mice (6-16 wks of age) show only subtle changes in
metabolic phenotype when fed a chow diet, e.g. slight
insulin resistance compared to WT mice[52; 55] or normal
insulin sensitivity[53], and no difference in body weight
and food intake[54]. In response to HFD (2 wks),
adiponectin KO mice display markedly greater fat mass,
insulin resistance, glucose intolerance, and chronic
inflammatory markers compared to WT littermates[52;
54-55]
. A recent study reported that adiponectin KO mice
developed marked fibrosingsteatohepatitis 40 wks after
HFD[56]. It would be interesting to explore whether
adiponectin KO mice will develop more AD related
pathology under chow and HFD conditions compared to
age matched WT control.
2) Commercially available adiponectin peptides for in
vitro or infusion studies
Adiponectin exists in different conformations
including trimer, hexamer and high-molecular weight
forms[57] as well as a globular isoform, which is produced
after proteolytic cleavage of full-length adiponectin

Zhongxiao Wan, et al.

Adiponectin as a link between obesity and AD
2.

decreased adiponectin secretion) owing to different

metabolic status are involved in the pathogenesis of AD.
Because depot-specific differences in adipose tissue
remain during the culture procedure[65], this approach will
be potentially helpful for determining whether fat from
different depots might have different roles in AD
pathology.

3.

4.

4. Final remarks
Given the alarming rates of obesity worldwide,
understanding the mechanisms underlying the increased
risk of AD in obesity is essential to develop
evidence-based therapies for mitigating AD risk.
Adiponectin may act locally or systemically, influencing
numoerous biological processes including energy
metabolism, insulin sensitivity, vascular function,
neuroendocrine function and immune responses. Several
different lines of evidence, from longitudinal cohort
studies in humans[47] to mechanistic studies in cell
culture[33-34] indicate that adiponectin exerts effects on the
brain, but data is still conflicting and further studies are
needed to clarify the precise actions of adiponectin in the
CNS. Elucidating the role of adiponectin in AD-related
pathology will hold promise for identifying potential
therapeutics (e.g. pharmacological induction of
adiponectin, targeted lifestyle strategies) that could
promote positive effects of adiponectin for the prevention
and/or treatment of AD and dementia in the context of
obesity.

5.

6.

7.

8.

9.

Conflicting Interests
10.

The authors declare they have no conflicting interests

Acknowledgements
Work in the corresponding authors laboratory is
supported by a Natural Sciences and Engineering
Research Council (NSERC) of Canada Discovery Grant.
ZW is supported by an Alzheimers Society Research
Program (ASRP) Postdoctoral Fellowship.

11.

12.
13.

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To cite this article: Wang Z, et al. Adiponectin and
Alzheimer's disease: Is there a link? Inflamm Cell Signal 2014;
1: e154. doi: 10.14800/ics.154.