Adiponectin in insulin resistance: lessons from translational research1–4
Florencia Ziemke and Christos S Mantzoros
Adiponectin is an adipose tissue–secreted endogenous insulin
sensitizer, which plays a key role as a mediator of peroxisome
proliferator-activated receptor c action. Adiponectin alters glucose
metabolism and insulin sensitivity, exhibits antiinflammatory and
antiatherogenic properties, and has been linked to several malig-
nancies. Circulating concentrations of adiponectin are determined
primarily by genetic factors, nutrition, exercise, and abdominal
adiposity.Adiponectin concentrations are lowerinsubjects withobe-
sity, metabolic syndrome, and cardiovascular disease. Adiponectin
knockout mice manifest glucose intolerance, insulin resistance, and
hyperlipidemia and tend to develop malignancies especially when on
high-fat diets. Animal studies have also shown beneficial effects of
tin are lower in patients with diabetes, cardiovascular disease, and
several malignancies. Studies to date provide promising results for
the diagnostic and therapeutic role of adiponectin in obesity, insulin
resistance, diabetes, cardiovascular disease, and obesity-associated
malignancies. Am J Clin Nutr 2010;91(suppl):258S–61S.
IDENTIFICATION AND MOLECULAR STRUCTURE
Adiponectin [also known as Acrp30 (adipocyte complement-
related protein of 30 kDa) or AdipoQ] is a 244–amino acid
protein secreted mainly by the adipose tissue. It was identified
almost simultaneously by 4 different groups in the mid-1990s as
an adipocyte-secreted hormone but remained in obscurity until
the early 2000s. Scherer et al (1) were the first to report isolating
adiponectin cDNA in mice by a differential display method in
adipocytes, and their data were soon thereafter confirmed by Hu
et al (2). Human adiponectin cDNA was also independently
identified from adipose tissue by Maeda et al (3), and human
adiponectin was finally purified from plasma by Nakano et al (4)
as a gelatin-binding protein. The adiponectin gene is located on
chromosome 3q26, a region associated with susceptibility to
developing metabolic syndrome and type 2 diabetes mellitus (5).
Adiponectin circulates in multimers, ie, as full-length or high-
molecular-weight (HMW), medium-molecular-weight (or hexamer),
and low-molecular-weight (or trimer) adiponectin complexes.
Additionally, full-length adiponectin may be cleaved to form a
smaller, globular fragment, which has been proposed to have
greater potency than full-length adiponectin (1). Adiponectin
contains an N-terminal collagen-like hypervariable region at the
NH2terminal and a C-terminal globular domain, which is similar
in structure to tumor necrosis factor-a, another adipose tissue–
secreted adipokine with an action opposite that of adiponectin (5).
Adiponectin primarily circulates in human plasma as a homomul-
timer or full-length structure (fAd or Acrp30). Posttranslational
modifications are critical determinants of activity, although con-
sensus on the biological activity of the specific circulating forms
of adiponectin is lacking. The HMW isoform was proposed to
have a stronger association with insulin resistance, metabolic
syndrome, and cardiovascular disease as the biologically more
active form of the hormone (7). We have shown, however, that
the additional predictive value provided by HMWadiponectin in
humans is minimal (6, 7).
REGULATION OF ADIPONECTIN EXPRESSION
Adiponectin is synthesized primarily in white adipose tissue
and, at lower concentrations, in brown adipose tissue (8). Much
lower concentrations of expression have been reported in skeletal
muscle, liver, colon, cardiac tissue, salivary glands, and placenta.
Adiponectin is even detected in cerebrospinal fluid and breast
milk at much lower concentrations (9). Normal plasma adipo-
nectin concentrations range between 5 and 30 lg/mL (depending
on the assay used), are 1000 time higher than leptin concen-
trations, and are inversely proportional to those of abdominal
adiposity (9), insulin resistance, and type 2 diabetes. Adiponectin
has also been shown to have distinct effects on lipid metabolism
as well as antiinflammatory and antiatherogenic effects (10). In
addition to its peripheral actions, adiponectin may act centrally
to modulate food intake and energy expenditure (11). Women
have higher adiponectin concentrations than do men (a measure
that is independent of fat mass or distribution), which is possibly
linked to differences in estrogen or androgen concentrations
(12). We have reported that in growing mice adiponectin initially
increases in proportion to accumulating adipose tissue until the
age of ’8–10 wk and then starts decreasing. Environmental
factors act as modulators of adiponectin (13), as shown by
a cross-sectional evaluation of diabetic women from the Nurses’
1From the Division of Endocrinology, Diabetes and Metabolism, Depart-
ment of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard
Medical School, Boston, MA.
2Presented at the symposium ‘‘Novel Therapeutic Advances through the
Development of Selective PPARc Modulators from Bench to Bedside,’’ held
at Experimental Biology 2009, New Orleans, LA, 21 April 2009.
3Supported by NIH/National Institute of Diabetes and Digestive and Kid-
ney Diseases grants R01DK079929, R01DK058785, K24DK081913, and
4Address correspondence to CS Mantzoros, Division of Endocrinology,
Diabetes and Metabolism, Beth Israel Deaconess Medical Center, 330
Brookline Avenue, Stoneman 816, Boston, MA 02215. E-mail: cmantzor@
First published online November 11, 2009; doi: 10.3945/ajcn.2009.28449C.
Am J Clin Nutr 2010;91(suppl):258S–61S. Printed in USA. ? 2010 American Society for Nutrition
Health Study that has linked a Mediterranean-type diet and its
components, primarily whole grains, moderate alcohol con-
sumption, and nuts, to higher adiponectin concentrations (14). A
recent prospective cohort study reports that coffee consumption
is associated with higher plasma adiponectin concentrations
(15). In vitro and in vivo studies in mice and humans have
shown that adiponectin expression and secretion is up-regulated
by thiazolidinediones (16–18) and/or selective peroxisome
proliferator-activated receptor c (PPARc) modulators, pre-
dominantly the HMW form. Although head-to-head comparisons
have not been performed, it appears that the selective PPARc
modulator INT131 is a relatively more potent enhancer of adi-
ponectin secretion (19).
Two different receptor isoforms, AdipoR1 and AdipoR2, have
been described to date (20). Both are 7-transmembrane proteins,
and in contrast to the G protein–coupled receptor family, these
receptors have internal N-terminal and external C-terminal re-
gions (20). AdipoR1 has a high affinity for globular adiponectin
and a low affinity for full-length adiponectin and is abundantly
expressed in skeletal muscle and endothelial cells among other
tissues. AdipoR2 has intermediate affinity for both forms of
adiponectin and is predominantly expressed in the liver (21, 22).
Although both receptors are present in almost every tissue, in-
cluding pancreatic b cells and malignant cells, one or the other
receptor usually predominates. Interestingly, HMW adiponectin
has also been proposed to be a ligand for T-cadherin, but this
remains to be fully elucidated.
Studies in mice link aging and high-fat feeding to increased
receptor expression in muscle and liver (P , 0.001) (23). We
have shown that both leptin and melanocortin agonists alter
AdipoR1/R2 expression in mice (24). Low adiponectin con-
centrations increase the risk of developing insulin resistance and
possibly diabetes (25). Yamauchi et al (26) observed in a lipo-
atrophic mouse model that replenishing physiologic doses of
adiponectin reverses insulin resistance. Adiponectin knockout
mice show increased platelet aggregation and thrombus forma-
tion, apoptosis, and tumor necrosis factor-a concentrations (27,
28). Adiponectin receptors are expressed in both fat and muscle
tissues in humans (27). We have also shown that both receptors
are expressed in subcutaneous and visceral adipose tissues and at
significantly lower concentrations (P , 0.001) than in skeletal
muscle. AdipoR1/R2 in muscle is inversely associated with cir-
culating adiponectin concentrations whereas AdipoR2 in sub-
cutaneous fat is positively associated with circulating adiponectin
concentrations (29, 30). Receptor expression in both fat and
muscle is further increased in insulin-resistant states accompanied
by hypoadiponectinemia. Physical activity up-regulates adipo-
nectin receptors (29), which suggests that the adiponectin hor-
mone system may mediate exercise-associated improvements in
insulin resistance (29, 30). Interestingly, PPARc agonists, used as
insulin sensitizers in the treatment of type 2 diabetes, stimulate
adiponectin production and secretion. More specifically, these
drugs (rosiglitazone, pioglitazone, and ciglitazone as well as the
selective PPARc model INT131) increase the HMW/total adipo-
nectin concentrations (19), but further clinical studies are needed
to investigate hypoadiponectimia in hyperinsulinemic states to
determine the potential therapeutic effects of this hormone.
Adiponectin binding to its receptors activates several in-
tracellular signaling pathways, mainly AMP-activated protein
kinase (AMPK) but also mTOR, nuclear transcription factor-jB
(NF-jB), STAT3, and JNK. AMPK phosphorylation promotes
glucose utilization that results in increased fatty acid oxidation,
increased glucose uptake in the muscle, and reduced gluco-
neogenesis in the liver. AMPK activation also regulates several
downstream targets, which include enzymes (involved in regu-
lating the synthesis of protein, fatty acids, and triglycerides such
as acetyl-CoA carboxylase and fatty acid synthase) as well as
transcription factors and other regulatory proteins. AMPK is an
upstream regulator of mTOR and is linked with several cancers
(31) by directly inhibiting this pathway that results in suppres-
sion of cell proliferation (32). The JNK- and STAT3-signaling
pathways are also proposed as mediators of adiponectin’s effects
on the metabolic syndrome and cancer (33).
OBESITY, METABOLIC SYNDROME, DIABETES, AND
Adiponectin concentrations are low in obese patients and
markedly increase after prolonged caloric restriction, such as in
dieting and anorexia nervosa (34), and are significantly lower
(P , 0.001) in obese subjects when compared with nonobese
males and females (35). Adiponectin is more closely associated
with visceral fat than with subcutaneous fat (12) and is lower in
type 2 diabetes, cardiovascular disease, hypertension, and met-
abolic syndrome (24, 35, 36), conditions that are often associated
with insulin resistance. A recent meta-analysis of prospective
studies with a total of 14,598 subjects and 2623 cases of type
2 diabetes indicated that higher adiponectin concentrations were
associated with a lower risk of type 2 diabetes. The estimated
absolute risk difference (cases/1000 person-years)/1-log lg/mL
increment in adiponectin concentrations was 3.9 for elderly
Americans and 30.8 for Americans with impaired glucose tol-
erance (36). Furthermore, adiponectin is positively correlated
with HDL cholesterol and negatively associated with serum tri-
glycerides and apolipoprotein B-100 (37). Adiponectin shows
antiinflammatory effects by enhancing nitric oxide production
and activating endothelial nitric oxide synthase (38) and may act
as a modulator of vascular remodeling by suppressing smooth
muscle cell migration (39), which possibly plays a role in the
regulation of atherosclerosis.
ADIPONECTIN AND CANCERS
We have proposed that adiponectin is a link between obesity
and obesity-related malignancies mainly on the basis of our
original observations thatadiponectin concentrations are lower in
patients with these types of cancers. Case-control studies con-
ducted by our group linked lower adiponectin concentrations to
an increased risk of breast cancer (40) and these observations
were later independently confirmed (42, 43). Similarly, the risk
of colorectal cancer has been inversely associated with lower
adiponectin in a prospective study in the context of the Health
(42,43),andthesefindingswerelaterconfirmedby a larger case-
control study nested within the European Prospective Inves-
tigation into Cancer and Nutrition Study (44). In addition,
several groups have reported similar inverse associations with
prostate cancer (45), myelodysplastic syndromes, a preleukemic
condition linked with obesity (46), as well as gastric (47) and
renal cancers. Lower concentrations of adiponectin were pos-
itively associated with renal cell carcinoma and tumor ag-
gression (48) and were shown to be even lower in patients with
In contrast, a hospital-based case-control study showed that adi-
ponectin concentrations are positively associated with pancreatic
cancer, and a substudy of tissue samples showed increased ex-
high adiponectin concentrations observed during cancer pro-
gression. Several single-nucleotide polymorphisms within the 5#
breast and colorectal cancer (51). Adiponectin’s direct effects are
exerted by receptor-mediated stimulation of signaling pathways
and indirectly by moderating insulin sensitivity at the level of
target tissue. Adiponectin acts through receptors R1/R2 to stim-
ulate signaling pathways, mainly AMPK, but also PPARa,
MAPK, and NF-kB (52). AMPK activation regulates cell pro-
liferation, decreases expression of transcriptional regulators, and
growth arrest and apoptosis (p21, p53). It is suggested that adi-
ponectin may regulate tumor cells by directly inhibiting pro-
angiogenic factors such as basic fibroblast growth factor and
interleukin-8 produced by tumors or platelet-derived growth
studies showed that adiponectin receptors, especially AdipoR1,
Mantzoros, unpublished data, 2009).
Adiponectin also exerts an indirect action through an insulin-
sensitizing, antiinflammatory, and antiangiogenic effect.
Hyperinsulinemia results in high concentrations of circulating
insulin-like growth factor I, which leads to increased cell pro-
liferation, decreased apoptosis, and increased inflammation (54).
In vitro studies to date show that adiponectin decreases cell
viability and proliferation in breast, colorectal, prostate, and
endometrial cancers. Recently, in vivo studies in mice evaluated
adiponectin’s role in suppression of colon cancer cell pro-
liferation and its possible therapeutic use for colon cancer (55).
Although promising, further studies are needed in animals and
humans to better delineate the effects of adiponectin and cell
proliferation, apoptosis, inflammation, and insulin sensitization
in relation to obesity-associated cancers.
CONCLUDING REMARKS AND FUTURE DIRECTION
Adiponectin, an endogenous insulin-sensitizing hormone and
the most abundant adipokine produced by the human adipose
tissue, is linked to obesity, metabolic syndrome, insulin re-
sistance, type 2 diabetes, and inflammation as well as several
types of cancers. Genetic factors such as single nucleotide
polymorphism 276 in the adiponectin gene and environmental
factors such as a high-fat diet and inactivity are associated with
low adiponectin concentrations and may contribute to the de-
velopment of insulin resistance, type 2 diabetes, and athero-
sclerosis. A Mediterranean-type diet, reduction of body weight,
and consumption of nuts, coffee, and/or moderate amounts
of alcohol have a well-established association with increased
plasma adiponectin concentrations and a decreased risk of de-
veloping insulin resistance, metabolic syndrome, diabetes, and
cardiovascular disease. More specifically, adiponectin could play
a potential role in the treatment of insulin-resistant states, which
include type 2 diabetes. Accumulating evidence from research
studies conducted in both animals and humans links adiponectin
and its receptors to several malignancies, which suggests a po-
tential role in regulating cell proliferation and a possible key role
in cancer prevention and/or therapy. Thus, adiponectin could
prove to be an effective therapeutic agent. Alternatively, phar-
macologic agents that could directly increase adiponectin’s cir-
culating concentrations (including novel or existing medications
on specific tissue targets, such as adiponectin receptor agonists
that induce signaling pathways downstream of adiponectin re-
ceptors, would be an important addition to our therapeutic ar-
mamentarium. (Other articles in this supplement to the Journal
include references 56–59.)
The authors’ responsibilities were as follows—FZ and CSM: wrote the
manuscript. FZ had no conflict of interest. CSM is the scientific cofounder
and Chair of the Scientific Advisory Board of InteKrin Metabolic Therapeu-
tics Inc, which has provided an unrestricted educational grant to support in
part this symposium.
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