S U P P L E M E N T

R e v i e w

Adipocytokines and the Metabolic Complications

of Obesity

Neda Rasouli and Philip A. Kern

The Central Arkansas Veterans Healthcare System (N.R.), and the Department of Medicine, Division of Endocrinology, University of
Arkansas for Medical Sciences (N.R., P.A.K.), Little Rock, Arkansas 72205

Context: Adipose tissue is increasingly recognized as an active endocrine organ with many secre-
tory products and part of the innate immune system. With obesity, macrophages infiltrate adipose
tissue, and numerous adipocytokines are released by both macrophages and adipocytes. Adipo-
cytokines play important roles in the pathogenesis of insulin resistance and associated metabolic
complications such as dyslipidemia, hypertension, and premature heart disease.

Evidence Acquisition: Published literature was analyzed with the intent of addressing the role of
the major adipose secretory proteins in human obesity, insulin resistance, and type 2 diabetes.

Evidence Synthesis: This review analyzes the characteristics of different adipocytokines, including
leptin, adiponectin, pro-inflammatory cytokines, resistin, retinol binding protein 4, visfatin, and
others, and their roles in the pathogenesis of insulin resistance.

Conclusions: Inflamed fat in obesity secretes an array of proteins implicated in the impairment of
insulin signaling. Further studies are needed to understand the triggers that initiate inflammation
in adipose tissue and the role of each adipokine in the pathogenesis of insulin resistance. (J Clin
Endocrinol Metab 93: S64 –S73, 2008)

M any recent epidemiological studies have documented the

rapid increase in the prevalence of obesity. According to
data from the Center for Disease Control Behavioral Risk Factor
Surveillance System, 22 states in the United States have an obesity
[body mass index (BMI) ⬎30 kg/m2] prevalence of over 30% in
2006, whereas only 10 yr earlier, no state had an obesity
prevalence of more than 20%. Along with the increase in
obesity is a parallel increase in the prevalence of type 2 dia-
betes, impaired glucose tolerance (1, 2), and other complica-
tions of obesity, such as hypertension, sleep apnea, and ar-
thritis. Whether or not the obesity epidemic leads to an
increase in the incidence of new obesity related malignancies
remains to be determined (3, 4). A recent study suggested that
future life expectancy may decrease for the first time due to the
increase in obesity (5).
The metabolic complications of obesity, often referred to as
the metabolic syndrome, consist of insulin resistance, often cul-
minating in ␤-cell failure, impaired glucose tolerance and type 2
diabetes, dyslipidemia, hypertension, and premature heart dis-
ease. Abdominal obesity, ectopic lipid accumulation, hepatic ste-
atosis, and sleep apnea can also be included in the metabolic
complications of obesity (6).
This paper is intended to provide an overview of the patho-
genesis of the metabolic complications of obesity, with particular
emphasis on the role of inflammation and adipose tissue-derived
proteins. There are many adipokines, and space limitations do
not permit a thorough discussion of all of them. Therefore, this
review will discuss a number of the major adipokines, and will
focus on adipokines related to inflammation, and in particular
adipokines that have been the subject of studies in humans, and
where there are clinical implications for obesity and insulin
resistance.
Obesity Is Associated with Inflammation
The role of adipose tissue in metabolic syndrome has continued
to evolve with the description of numerous secretory products
from adipocytes. These “adipokines” are important determi-

0021-972X/08/$15.00/0 Abbreviations: AMPK, AMP-activated protein kinase; BMI, body mass index; ER, endo-
Printed in U.S.A. plasmic reticulum; Glut4, glucose transporter 4; HMM, high-molecular mass; MCP, mono-
cyte chemoattractant protein; PAI-1, plasminogen activator inhibitor 1; PPAR, peroxisome
Copyright © 2008 by The Endocrine Society proliferator activated receptor; RBP4, retinol binding protein 4; STAT3, signal transducer
doi: 10.1210/jc.2008-1613 Received July 25, 2008. Accepted September 15, 2008. and activator of transcription-3; TSP, thrombospondin; TZD, thiazolidinedione.

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J Clin Endocrinol Metab, November 2008, 93(11):S64 –S73
nants of insulin resistance, either through a traditional (circu-
lating) hormonal effect, or through local effects on the adipocyte.
In the mid-1990s, the expression of TNF␣ by adipose tissue
of obese rodents and humans was first described (7, 8). Subse-
quently, other adipose tissue-derived proteins were described, and
many of these adipokines have been implicated in the pathogenesis
of the chronic inflammation and insulin resistance associated with
obesity. In addition to the production of pro-inflammatory cyto-
kines that promote metabolic complications, adipose tissue is the
sole source of adiponectin, which is antiinflammatory and associ-
ated with protection from atherosclerosis (9, 10).
The study of adipose tissue inflammation was considerably
impacted by the demonstration of resident macrophages in ad-
ipose tissue (11, 12). The adipose tissue of obese rodents and
humans contains increased numbers of macrophages, and once
activated, macrophages secrete a host of cytokines such as
TNF␣, IL-6, and IL-1 (13), and the adipose tissue resident mac-
rophages were responsible for the expression of most of the tissue
TNF␣ and IL-6. The expression of macrophage markers in hu-
man adipose tissue was high in subjects with obesity and insulin
resistance, and was also correlated with the expression of TNF␣
and IL-6 (12, 14).
There are a number of possible mechanisms underlying the
infiltration of macrophages into adipose tissue. One possibility
is the elaboration of chemokines by adipocytes, which would
then attract resident macrophages. Adipocytes express low levels
of monocyte chemoattractant protein (MCP)-1, and increased
expression is found in obese subjects (14). From an evolutionary
perspective, adipose macrophages may have represented an im-
portant part of the host defense against injury or infection. On
the other hand, recent studies have suggested that macrophages
infiltrate adipose tissue as part of a scavenger function in re-
sponse to adipocyte necrosis. Careful immunohistological stud-
ies of mouse and human adipose tissue demonstrated that most
of the macrophages in adipose tissue of obese mice were sur-
rounding dead adipocytes and formed a syncytium, often re-
ferred to as a “crown-like structure” (15). With the rapid devel-
opment of obesity in both diet and genetically obese rodent
models, the number of crown-like structures in adipose tissue
increases rapidly, and the macrophage burden surrounding ne-
crotic adipocytes becomes considerable (16).
If adipocyte necrosis is indeed the initiating event in the pro-
cess of macrophage infiltration, there are a number of possible
causes. Hypoxia has been proposed to be an inciting etiology of
necrosis (17). With obesity and progressive adipocyte enlarge-
ment, the blood supply to adipocytes may be reduced (18), and
the induction of adipocyte hypoxia in vitro results in the expres-
sion of a number of inflammatory cytokines (19 –21). Indeed, an
increased prevalence of insulin resistance in patients with sleep
apnea independent of obesity has been reported, which is per-
haps due to intermittent hypoxia, inflammation, and oxidative
stress (22).
Another body of thought suggests that unbridled adipocyte
expansion and triglyceride accumulation in adipose tissue are
ultimately a benign phenomenon, and perhaps even beneficial to
relieve lipotoxicity in liver, skeletal muscle, and other ectopic
sites (23). Adipose tissue inflammation may occur when adipo-
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jcem.endojournals.org S65
cyte expansion is limited, either due to impaired adipocyte de-
velopment, decreased lipid synthesis, or matrix factors that pre-
vent cell enlargement. One example of limited adipocyte
development is lipodystrophy. Humans and rodents with ex-
treme forms of lipodystrophy have little or no adipose tissue and
extreme ectopic fat deposition, leading to lipotoxicity and insulin
resistance (24). However, lesser degrees of lipodystrophy occur
in patients with HIV lipodystrophy, who demonstrate features of
the metabolic syndrome. The adipose tissue of HIV-infected pa-
tients demonstrated increased inflammation and lower levels of
expression of lipin-␤ (25–28). Lipin is a phosphatidate phospha-
tase involved in lipid synthesis, and animals with lipin deficiency
are lipodystrophic (29, 30). In addition, lower levels of adipose
lipin expression are found in non-HIV infected subjects with
insulin resistance, and peroxisome proliferator activated recep-
tor (PPAR)-␥ agonists increase the expression of the ␤-isoform of
lipin (31). Other genes involved in adipocyte differentiation or
lipogenesis may also be associated with adipose tissue inflam-
mation. Therefore, the association of obesity with insulin resis-
tance and inflammation is well established. The concept of lim-
ited adipocyte expansion, leading to inflammation and many of
the metabolic consequences of obesity, is somewhat counterin-
tuitive, but enjoys some support in the literature. This concept
clearly needs further development and clarification with future
research.
Adipokines Expressed by Adipocytes
Leptin
Leptin (Greek, leptos, thin), is a 167-amino acid hormone
secreted largely by adipose tissue that controls food intake and
energy expenditure (32). Circulating levels of leptin parallel fat
cell stores, increasing with overfeeding and decreasing with star-
vation. The absence of leptin or a mutation in leptin receptor
genes induces a massive hyperphagia and obesity in animal mod-
els (33), and humans (34, 35), however, the prevalence of these
mutations in obese humans is rare.
The effects of leptin are mediated by receptors, mainly located
in the central nervous system, and in other tissues, including
adipocytes and endothelial cells. Leptin receptor belongs to the
class I family of cytokine receptors, and it engages both the signal
transducer and activator of transcription-3 (STAT3) pathway
and the insulin receptor substrate phosphoinositide-3 kinase
pathway, among others (36). It has been shown that STAT3 is
essential for mediating food intake, liver glucose production, and
gonadotropin secretion (36), however, the control of adipose
tissue metabolism by leptin is STAT3 independent (37). Re-
cently, Buettner et al. (37) showed that the infusion of leptin in
hypothalamus led to the suppression of lipogenesis in adipose
tissue through activation of the phosphoinositide-3 kinase path-
way, sympathic nervous system, and the engagement of adipose
tissue endocannabinoid system.
Other potential physiological roles for leptin have been de-
scribed. Leptin modulates the T-cell immune response, stimu-
lates proliferation of T-helper cells, and increases production of
pro-inflammatory cytokines by regulating different immune cells
S66 Rasouli and Kern Adipocytokines and Obesity
(38, 39). Leptin is also important in regulating the reproductive
system and the onset of puberty, and leptin deficiency is associ-
ated with hypogonadism (40).
The increased risk of cardiovascular disease with obesity
makes adipokines, including leptin, an attractive instigator of
atherosclerosis. In a large prospective study, leptin was indepen-
dently associated with an increased risk of coronary artery dis-
ease (41). However, the question whether leptin directly causes
atherosclerosis in obese individuals is still unresolved. In in vitro
or animal studies, different atherogenic properties, including in-
creased oxidative stress, impairment of vasorelaxation, and in-
creased thrombosis, have been described for leptin (42, 43).
Potential use of leptin as a drug
Treatment with recombinant human leptin reverses hy-
perphagia, obesity, hypogonadism, and impaired T-cell-medi-
ated immunity associated with congenital leptin deficiency (44,
45). In addition, leptin replacement is a very promising thera-
peutic approach for the management of the complications of
lipodystrophy (46). In contrast, leptin treatment for the reversal
of typical obesity and obesity related metabolic disorders has not
proven to be successful (47). Obese individuals, for unknown
reasons, become resistant to the satiety and weight-reducing ef-
fect of leptin. A recent study reported a synergistic effect for
weight loss with leptin and amylin coadministration in diet-in-
duced obese rats by restoring hypothalamic sensitivity to leptin
(48). If confirmed in clinical research studies, the restoration of
leptin sensitivity might change the neurohormonal approaches
to obesity pharmacotherapy.
Adiponectin
Adiponectin is a 30-kDa protein secreted from adipocytes (9),
and its circulating levels are decreased in obesity induced insulin
resistance (49, 50). Paradoxically, in rare cases of severe insulin
resistance with proximal defect in insulin action, elevated levels
of adiponectin have been reported (51). Mice lacking adiponec-
tin have reduced insulin sensitivity (52–54); in contrast, adi-
ponectin overexpression in ob/ob mice, confers dramatic meta-
bolic improvements (23).
Once adiponectin is synthesized, it undergoes several post-
translational modifications, including hydroxylation and glyco-
sylation (55), and some of these modifications are necessary for
its bioactivity (56). Circulating adiponectin is found in several
different isoforms, including trimer, low-molecular weight
(-hexamers), and high-molecular weight (HMW) (18mers)
forms (57, 58). Different adiponectin oligomers hold distinct
biological functions. Most insulin-sensitizing effects of adi-
ponectin have been linked to the HMW isoform, whereas the
central effects of adiponectin have been contributed to hexamer
and trimer isoforms (55).
The distribution of adiponectin oligomers in the circulation is
primarily controlled at the level of secretion from adipocytes.
Molecular chaperones in the endoplasmic reticulum (ER), in-
cluding ER protein of 44 kDa and ER oxidoreductase 1-L␣, play
an important role in the secretion of adiponectin (55, 63).
Several studies have linked hypoadiponectinemia to diabetes
(50), hypertension (59), atherosclerosis, and endothelial dys-
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J Clin Endocrinol Metab, November 2008, 93(11):S64 –S73
function (60). More recent studies have shown that the HMW
oligomer is inversely associated with the risk for diabetes inde-
pendent of total adiponectin (61), and the HMW oligomer is
responsible for the association of adiponectin with traits of met-
abolic syndrome (62, 63).
Adiponectin inserts its effects through two transmembrane
receptors (AdipoR1 and AdipoR2) that are ubiquitously ex-
pressed. AdipoR1 is predominantly expressed in skeletal muscle
with a preference for binding to globular adiponectin, whereas
AdipoR2 is most abundant in the liver with a preference for
binding to full-length adiponectin (64). Adiponectin improves
insulin sensitivity by increasing energy expenditure and fatty acid
oxidation through activation of AMP-activated protein kinase
(AMPK), and by increasing the expression of PPAR␣ target genes
such as CD36, acyl-coenzyme oxidase, and uncoupling protein
2 (60). Alternatively, adiponectin may lead to an improved met-
abolic profile by the expansion of sc adipose tissue with de-
creased levels of macrophage infiltration (23), similar to the ac-
tions of PPAR␥ agonists. Thiazolidinediones (TZDs) are known
to increase circulating levels of adiponectin, mostly the HMW
form, by 2- to 3-fold (65– 67), and improve insulin resistance by
diversion of fat from ectopic sites to sc adipose tissue (68). In-
terestingly, insulin-sensitizing effects of TZDs are significantly
diminished in the absence of adiponectin (54), suggesting an
important role of adiponectin in reduction of lipotoxicity and
inflammation associated with obesity.
Adiponectin has also had vasculoprotective effects mediated
via an increase in endothelial nitric oxide production, or mod-
ulation of expression of adhesion molecules and scavenger re-
ceptors (60, 69).
In addition to peripheral actions, it has been suggested that
adiponectin has central effects in the regulation of energy ho-
meostasis (70). Adiponectin was present in cerebrospinal fluid
largely in the form of trimer and hexamer, in contrast to the
distribution of adiponectin in serum, which consists of higher
molecular masses (71). It has been proposed that adiponectin
increases food intake by enhancing hypothalamic AMPK activity
in fasting conditions (72).
Resistin
Resistin is a 12-kDa peptide that was originally discovered as
a result of examining differential gene expression of mouse ad-
ipose tissue after TZD treatment (73). Resistin is part of a gene
family of “Resistin-like molecules,” and is increased along with
PPAR␥ during the differentiation of 3T3-L1 adipocytes (74).
Resistin was decreased by TZD treatment of mice and was in-
creased in insulin-resistant mice. Furthermore, treatment with
antiresistin antibody improved insulin sensitivity and glucose
transport in mice and mouse adipocytes, respectively (73). Ad-
ditional studies in mice suggest that an important site of action
of resistin is on hepatic glucose production (75). Although these
data in mice are exciting, the role of resistin in human insulin
resistance is less clear. Resistin is expressed by adipocytes in mice
but is expressed by the macrophages of humans (76). A number
of studies have examined plasma resistin levels or adipose resistin
expression, and have found variable associations with insulin
resistance (77– 80). A recent large study involving the Framing-
J Clin Endocrinol Metab, November 2008, 93(11):S64 –S73
ham offspring cohort found a significant relationship between
insulin resistance and resistin, however, this relationship was
considerably weaker than the relationship with adiponectin, and
was lost after adjustment for BMI (81). Resistin decreases after
TZD treatment of humans, although resistin was also decreased
by metformin treatment (65, 82). Therefore, resistin is clearly an
important adipokine that likely plays a role in the development
of insulin resistance; however, it appears to be quantitatively less
important in humans than other adipokines.
Retinol binding protein 4 (RBP4)
One interesting rodent model of insulin resistance is the ad-
ipose tissue-specific glucose transporter 4 (Glut4) knockout
mouse (83), in which the defect in adipose tissue glucose trans-
port yielded peripheral insulin resistance, apparently due to a
circulating factor. RBP4 was identified as a highly expressed
circulating adipokine in this model and caused insulin resistance
when overexpressed or injected into mice (84). Since that time,
a number of human studies have been performed that examined
RBP4 protein levels in circulation and/or its gene expression in
adipose tissue in subjects with varying degrees of obesity, insulin
resistance, or type 2 diabetes. Some papers demonstrated a pos-
itive association between RBP4 and insulin resistance or obesity
(84 –94), sometimes with strikingly strong correlations, whereas
others have not found such a relationship (95–100). One study
found no relationship between RBP4 and insulin sensitivity in
older subjects, but a weak relationship in young subjects, sug-
gesting an age-related difference (101). Another study found no
significant relationship between RBP4 and insulin sensitivity,
but RBP4 was associated with adipose tissue macrophage mark-
ers, suggesting a possible role of RBP4 in inflammation (95). The
response to TZDs has been examined in fewer studies, and again
the response was inconsistent. If RBP4 is associated with insulin
resistance, one would expect a decrease after treatment with rosi-
or pioglitazone. Such a response was found in Glut4 knockout
mice (84) and in some human studies (90, 91, 102, 103). How-
ever, in other studies, human subjects treated with TZDs dem-
onstrated no change or an increase in RBP4 mRNA (94, 95), and
the addition of pioglitazone to adipocytes in vitro also resulted
in increased RBP4 mRNA (95). RBP4 circulates bound to tran-
sthyretin, which decreases RBP4 renal clearance, and transthy-
retin plasma levels were increased 4-fold in ob/ob mice compared
with lean mice or diet-induced obese mice (104). Although
RBP4-transthyretin binding may be important physiologically,
this area needs further study. Thus, the data are currently con-
flicting on the role of RBP4 in insulin resistance and the meta-
bolic complications of obesity. Because of the association with
Glut4, RBP4 is presumed to play a role in fuel sensing in the
adipocyte, but in other respects, a possible mechanism for caus-
ing insulin resistance is not clear.
Visfatin
Visfatin is expressed in many cells and tissues, and was pre-
viously identified as a protein involved in B-cell maturation
(pre-B colony enhancing factor) (105, 106). More recently, vis-
fatin was described to be a highly expressed protein with insulin-
like functions, and was predominantly found in visceral adipose
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jcem.endojournals.org S67
tissue, from which the name visfatin was derived (107). Injection
of visfatin in mice lowered blood glucose, and mice with a mu-
tation in visfatin had higher glucose levels.
Although these initial studies were promising, subsequent
studies of visfatin in humans have generally not confirmed the
initial study, which was, in part, retracted (108). A subsequent
study did not confirm the insulin mimetic action of visfatin but
instead demonstrated that visfatin has nicotinamide adenine
dinucleotide (NAD) biosynthetic activity, which is essential for
B-cell function (109). In human studies, a positive correlation
between visceral adipose tissue visfatin gene expression and BMI
was noted, along with a negative correlation between BMI and
sc fat visfatin (110, 111), suggesting that visfatin regulation in
these different depots is different, and adipose depot ratios are
highly dependent on the obesity of the subjects. No difference in
visfatin expression between fat depots of humans was noted
(110, 111), and visfatin was expressed predominantly by non-
macrophage cells in the adipose tissue stroma (111). Plasma vis-
fatin was positively associated with BMI in one study (110), but
not in others (111, 112). Variable results were obtained regard-
ing the relationship between visfatin and diabetes or insulin re-
sistance (111–114), and visfatin was not responsive to PPAR␥
agonists and was not correlated with macrophage markers (111).
Therefore, there are a number of inconsistencies among the dif-
ferent studies of visfatin, and the role of this adipokine in obesity
and insulin resistance is not clear.
Inflammatory Cytokines Produced by
Macrophages
Obesity is characterized by increased fat mass frequently asso-
ciated with chronic inflammation. Yet, the mechanisms trigger-
ing the inflammatory pathway in obesity are to be determined,
and discussed previously. An increased number of macrophages
resident in human adipose tissue has been reported in obesity
(14) that may contribute to the inflammatory process by secret-
ing pro-inflammatory cytokines such as TNF␣, IL6, and MCP-1.
In addition to increased infiltration of macrophages in adipose
tissue, obesity is associated with changes in the phenotype of
macrophages from alternatively activated toward a more clas-
sical and pro-inflammatory cell (115) as the source of pro-in-
flammatory mediators. Inactivation of the nuclear factor-␬B
pathway, which induces inflammatory mediators, has led to the
protection against insulin resistance (116).
TNF␣
Of the pro-inflammatory cytokines, TNF␣ is well described
to disturb insulin signaling. Mice lacking TNF␣ or TNF␣ recep-
tors are resistant to the development of obesity induced insulin
resistance (117, 118). In adipose tissue, TNF␣ is mostly secreted
by macrophages in the stromal vascular fraction. Circulating
TNF␣ and adipose tissue TNF␣ gene expression are increased in
insulin resistance (119), and acute infusion of TNF␣ inhibited
insulin-induced glucose uptake in healthy subjects (120). Neu-
tralization of TNF␣ in rodents has improved insulin resistance
(7), whereas attempts to neutralize TNF␣ in humans to improve
S68 Rasouli and Kern Adipocytokines and Obesity
PPARγ
agonists
PAI-1
TSP1 TGFβ
activation
TNFα
insulin
High glucose
Angiotensin II
FIG. 1. Role of TSP1, TGF-␤, and PAI-1 in adipose tissue. TSP1 is expressed by adipose tissue, and activates
TGF-␤, which in turn activates PAI-1, which is a procoagulant. TGF-␤ is also activated by high glucose and
angiotensin II. TSP1 expression is inhibited by PPAR␥ agonists, which may explain some of the beneficial
effects of these drugs.
insulin resistance have generally not been successful (121), al-
though more recent studies have shown slight improvement in
insulin resistance with TNF␣ inhibition (122–124). Limited ef-
fects of TNF␣ blockade on insulin resistance could be explained
by the paracrine actions of TNF␣. Further investigations on the
mechanisms involved in TNF␣ overexpression associated with
obesity and molecular signals underlying TNF␣-induced meta-
bolic dysregulation are warranted.
IL-6
IL-6 is another cytokine similar to TNF␣ that is overex-
pressed in the adipose tissue of obesity (119). The role of IL-6 in
metabolic changes associated with obesity is unclear. There are
some reports of IL-6 causing impaired insulin signaling in the
liver and adipocytes by inducing ubiquitin-mediated degrada-
tion of insulin receptor substrate through suppressor of cytokine
signaling (SOCS) 1 and 3 (125, 126). However, effects of IL-6 on
insulin sensitivity in skeletal muscle is controversial (126). Ex-
ercise that is associated with increased insulin action in skeletal
muscle increases circulating IL-6 levels dramatically (127), sug-
gesting possible antiinflammatory roles for IL-6 in skeletal mus-
cle. The data on the increased onset of obesity and diabetes in
mice lacking IL-6 are conflicting (128, 129).
MCPs
As discussed previously, infiltration of macrophages into ad-
ipose tissue is an important contributor of the increased inflam-
matory process in obesity. Adipocytes secrete various chemoat-
tractants that draw monocytes from circulation into adipose
tissue. MCP-1, also known as chemokine (C-C motif) ligand 2
(CCL-2), is one the chemoattractants that plays an important
role in the recruitment of macrophages. Moreover, obesity is
associated with increased plasma levels of MCP-1 and overex-
pression in adipose tissue (14, 130). Mice lacking MCP-1 recep-
tor (CCR-2) have decreased adipose tissue macrophage infiltra-
tion and improved metabolic function (12). Similarly, it has been
demonstrated that mice lacking MCP-1 have reduced adipose
tissue macrophage infiltration (131), however, a more recent
study did not confirm this finding (132). This suggests that there
are other candidates that might play a role in the recruitment of
macrophages into the adipose tissue, such as macrophage in-
flammatory protein-1␣ (11) or osteopontin (133, 134). Os-
teopontin is an extracellular matrix protein that promotes mono-
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J Clin Endocrinol Metab, November 2008, 93(11):S64 –S73
cyte chemotaxis, and the lack of
Atherosclerosis osteopontin in mice caused improved in-
sulin sensitivity and decreased macro-
Fibrosis
phage infiltration into adipose tissue (134).
Impairs insulin
action
Procoagulation
Adipokines Involved with
Thrombosis:
Thrombospondin (TSP) and
Plasminogen Activator
Inhibitor 1 (PAI-1)
PAI-1 is elevated in subjects with meta-
bolic complications of obesity, and is ex-
pressed in the stromal fraction of adipose tissue, including en-
dothelial cells (135–139). PAI-1 inhibits both tissue-type
plasminogen activator and urokinase-type plasminogen activa-
tor through its serine protease inhibitor function, and this inhi-
bition of fibrinolysis may contribute to a pro-thrombotic state
(140).
PAI-1 gene expression is controlled by TGF-␤, which com-
bines with phosphorylated SMAD and binds to the PAI-1 pro-
moter (141). Another important link in PAI-1 activation was the
recent demonstration of TSP1 expression in adipocytes (142).
TSP1 is expressed by many tissues, and has many different ac-
tivities, including inhibition of angiogenesis, cell proliferation,
and wound healing (143, 144). TSP1 is a major activator of
TGF-␤ (145), and PAI-1 activation by TSP1 has been described
(146) (Fig. 1).
A recent study demonstrated TSP1 expression largely by adi-
pocytes compared with the stromal vascular fraction of adipose
tissue, suggesting that TSP1 is a true adipokine (142). TSP1 ex-
pression was increased in obese, insulin-resistant subjects, was
associated with plasma PAI-1 levels, and was positively associ-
ated with adipose tissue macrophage markers. In addition, TSP1
expression was decreased by treatment of subjects or adipocytes
with the PPAR␥ agonist, pioglitazone. TSP1 has chemotactic
properties (143) that provide a link between TSP1 and macroph-
age-mediated adipocyte inflammation. In addition, adipocyte-
macrophage coculture experiments demonstrated TSP1 gene
and protein up-regulation by both cells, suggesting a feed-for-
ward inflammatory mechanism in adipose tissue (142). TSP1
may be an important component of inflammation and coagula-
tion in the metabolic complications of obesity.
Summary
Adipose tissue was once recognized simply as an inert storage
organ, but now is appreciated increasingly as an endocrine organ
and part of an innate immune system. Factors secreted from
adipose tissue contribute considerably to the regulation of me-
tabolism and inflammatory responses. The adipose tissue of in-
sulin-sensitive humans secretes adiponectin abundantly, which is
associated with a favorable metabolic condition. However, with
adiposity, adiponectin secretion decreases significantly, and
multiple adipocyte-derived factors induce activation and infil-
J Clin Endocrinol Metab, November 2008, 93(11):S64 –S73 jcem.endojournals.org S69

visfatin leptin RBP4

resistin
PAI, TSP1

obesity

TZD
Lean/healthy fat

Expandable fat
Obese/Inflamed fat ↓FFA
adiponectin
↓TNF, IL6
IL6
TNF
FFA ↑↑adiponectin
PPARα AMPK

↓adiponectin
β oxidation
Ectopic lipid

FIG. 2. Changes in adipose tissue, liver, and muscle with obesity and insulin resistance. The adipose tissue of lean subjects contains few macrophages, and secretes
relatively high levels of adiponectin, and low levels of inflammatory cytokines. ␤-Oxidation of lipids in muscle is high, and there is little ectopic fat in the muscle and
liver. With obesity and insulin resistance, adipose tissue contains many macrophages, and the tissue secretes high levels of many adipokines, and low levels of
adiponectin. This adipose tissue may be limited in its lipid storage capacity, and this feature, along with the pro-inflammatory state, promotes ectopic lipid
accumulation. The adipose tissue in some subjects can be characterized as expandable, meaning the tissue can accommodate more lipid. This may result from
treatment with a TZD. Such adipose tissue may be less inflamed, and because this adipose tissue can accumulate more lipid, there is less ectopic fat.

tration of macrophage into adipose tissue. Activated macro- References

phages secrete cytokines that can contribute to more macro-
phage infiltration. As shown in Fig. 2, inflamed fat in obesity
secretes an array of proteins implicated in the impairment of
insulin signaling. In addition, in a hypothetical model, inflamed
fat releases more free fatty acids that contribute to fat accumu-
lation in ectopic sites, including liver and muscle. Increased lipid
content in liver and muscle has been associated with insulin re-
sistance. PPAR␥ ligands, such as TZDs, improve insulin resis-
tance through multiple potential mechanisms. PPAR␥ agonists
enhance adipogenesis, increase adiponectin, and exert antiin-
flammatory effects on macrophages resident in adipose tissue.
Future studies are needed to focus on the factors initiating the
inflammatory process in adipose tissue and the regulation of
adipocyte secretory products.
Acknowledgments
Address all correspondence and requests for reprints to: Philip A. Kern,
M.D., Slot 718, University of Arkansas for Medical Sciences, 4301
Markham Street, Little Rock, Arkansas 72205. E-mail: KernPhilipA@
uams.edu.
This work was supported by Merit Review Grant from the Veterans
Administration (to N.R.), and DK71277 and DK080327 from the
National Institutes of Health (to P.A.K.).
Disclosure Statement: P.A.K. and N.R. have received honoraria for
speaking from Takeda Pharmaceuticals.
1. Harris MI, Flegal KM, Cowie CC, Eberhardt MS, Goldstein DE, Little RR,
Wiedmeyer HM, Byrd-Holt DD 1998 Prevalence of diabetes, impaired fast-
ing glucose, and impaired glucose tolerance in U.S. adults. The Third National
Health and Nutrition Examination Survey, 1988 –1994. Diabetes Care 21:
518 –524
2. Harris MI 1998 Diabetes in America: epidemiology and scope of the problem.
Diabetes Care 21(Suppl 3):C11–C14
3. Rose DP, Haffner SM, Baillargeon J 2007 Adiposity, the metabolic syndrome,
and breast cancer in African-American and white American women. Endocr
Rev 28:763–777
4. Bray GA 2004 Medical consequences of obesity. J Clin Endocrinol Metab
89:2583–2589
5. Olshansky SJ, Passaro DJ, Hershow RC, Layden J, Carnes BA, Brody J,
Hayflick L, Butler RN, Allison DB, Ludwig DS 2005 A potential decline in
life expectancy in the United States in the 21st century. N Engl J Med 352:
1138 –1145
6. Parati G, Lombardi C, Narkiewicz K 2007 Sleep apnea: epidemiology, patho-
physiology, and relation to cardiovascular risk. Am J Physiol Regul Integr
Comp Physiol 293:R1671–R1683
7. Hotamisligil GS, Shargill NS, Spiegelman BM 1993 Adipose expression of
tumor necrosis factor-␣: direct role in obesity-linked insulin resistance. Sci-
ence 259:87–91
8. Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB 1995 The
expression of tumor necrosis factor in human adipose tissue. Regulation by
obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest 95:
2111–2119
9. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF 1995 A novel
serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem
270:26746 –26749
10. Kumada M, Kihara S, Sumitsuji S, Kawamoto T, Matsumoto S, Ouchi N,
Arita Y, Okamoto Y, Shimomura I, Hiraoka H, Nakamura T, Funahashi T,
Matsuzawa Y, Osaka CAD Study Group, Coronary artery disease 2003 As-

Downloaded from jcem.endojournals.org at Universidad de Chile on January 5, 2009

S70 Rasouli and Kern Adipocytokines and Obesity
sociation of hypoadiponectinemia with coronary artery disease in men. Ar-
terioscler Thromb Vasc Biol 23:85– 89
11. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross
JS, Tartaglia LA, Chen H 2003 Chronic inflammation in fat plays a crucial
role in the development of obesity-related insulin resistance. J Clin Invest
112:1821–1830
12. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW
2003 Obesity is associated with macrophage accumulation in adipose tissue.
J Clin Invest 112:1796 –1808
13. Wellen KE, Hotamisligil GS 2003 Obesity-induced inflammatory changes in
adipose tissue. J Clin Invest 112:1785–1788
14. Di Gregorio GB, Yao-Borengasser A, Rasouli N, Varma V, Lu T, Miles LM,
Ranganathan G, Peterson CA, McGehee RE, Kern PA 2005 Expression of
CD68 and macrophage chemoattractant protein-1 genes in human adipose
and muscle tissues: association with cytokine expression, insulin resistance,
and reduction by pioglitazone. Diabetes 54:2305–2313
15. Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S,
Greenberg AS, Obin MS 2005 Adipocyte death defines macrophage local-
ization and function in adipose tissue of obese mice and humans. J Lipid Res
46:2347–2355
16. Strissel KJ, Stancheva Z, Miyoshi H, Perfield JW, DeFuria J, Jick Z, Greenberg
AS, Obin MS 2007 Adipocyte death, adipose tissue remodeling, and obesity
complications. Diabetes 56:2910 –2918
17. Trayhurn P, Wood IS 2004 Adipokines: inflammation and the pleiotropic
role of white adipose tissue. Br J Nutr 92:347–355
18. Rausch ME, Weisberg S, Vardhana P, Tortoriello DV 2008 Obesity in
C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell
infiltration. Int J Obes (Lond) 32:451– 463
19. Trayhurn P, Wang B, Wood IS 2008 Hypoxia in adipose tissue: a basis for the
dysregulation of tissue function in obesity? Br J Nutr 100:227–235
20. Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K,
Furukawa S, Tochino Y, Komuro R, Matsuda M, Shimomura I 2007
Adipose tissue hypoxia in obesity and its impact on adipocytokine dys-
regulation. Diabetes 56:901–911
21. Wang B, Wood IS, Trayhurn P 2007 Dysregulation of the expression and
secretion of inflammation-related adipokines by hypoxia in human adipo-
cytes. Pflugers Arch 455:479 – 492
22. Lam JC, Ip MS 2007 An update on obstructive sleep apnea and the metabolic
syndrome. Curr Opin Pulm Med 13:484 – 489
23. Kim JY, van de WE, Laplante M, Azzara A, Trujillo ME, Hofmann SM,
Schraw T, Durand JL, Li H, Li G, Jelicks LA, Mehler MF, Hui DY, Deshaies
Y, Shulman GI, Schwartz GJ, Scherer PE 2007 Obesity-associated improve-
ments in metabolic profile through expansion of adipose tissue. J Clin Invest
117:2621–2637
24. Agarwal AK, Garg A 2006 Genetic disorders of adipose tissue development,
differentiation, and death. Annu Rev Genomics Hum Genet 7:175–199
25. Giralt M, Domingo P, Guallar JP, Rodriguez de la Concepcion ML, Alegre M,
Domingo JC, Villarroya F 2006 HIV-1 infection alters gene expression in
adipose tissue, which contributes to HIV-/HAART-associated lipodystrophy.
Antivir Ther 11:729 –740
26. Johnson JA, Albu JB, Engelson ES, Fried SK, Inada Y, Ionescu G, Kotler DP
2004 Increased systemic and adipose tissue cytokines in patients with HIV-
associated lipodystrophy. Am J Physiol Endocrinol Metab 286:E261–E271
27. Lagathu C, Kim M, Maachi M, Vigouroux C, Cervera P, Capeau J, Caron M,
Bastard JP 2005 HIV antiretroviral treatment alters adipokine expression and
insulin sensitivity of adipose tissue in vitro and in vivo. Biochimie 87:65–71
28. Lindegaard B, Larsen LF, Hansen AB, Gerstoft J, Pedersen BK, Reue K 2007
Adipose tissue lipin expression levels distinguish HIV patients with and with-
out lipodystrophy. Int J Obes (Lond) 31:449 – 456
29. Donkor J, Sariahmetoglu M, Dewald J, Brindley DN, Reue K 2007 Three
mammalian lipins act as phosphatidate phosphatases with distinct tissue ex-
pression patterns. J Biol Chem 282:3450 –3457
30. Phan J, Reue K 2005 Lipin, a lipodystrophy and obesity gene. Cell Metab
1:73– 83
31. Yao-Borengasser A, Rasouli N, Varma V, Miles LM, Phanavanh B, Starks
TN, Phan J, Spencer III HJ, McGehee Jr RE, Reue K, Kern PA 2006 Lipin
expression is attenuated in adipose tissue of insulin-resistant human subjects
and increases with peroxisome proliferator-activated receptor ␥ activation.
Diabetes 55:2811–2818
32. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM 1994
Positional cloning of the mouse obese gene and its human homologue. Nature
372:425– 432
33. Friedman JM, Halaas JL 1998 Leptin and the regulation of body weight in
mammals. Nature 395:763–770
34. Farooqi IS, Wangensteen T, Collins S, Kimber W, Matarese G, Keogh JM,
Downloaded from jcem.endojournals.org at Universidad de Chile on January 5, 2009
J Clin Endocrinol Metab, November 2008, 93(11):S64 –S73
Lank E, Bottomley B, Lopez-Fernandez J, Ferraz-Amaro I, Dattani MT, Er-
can O, Myhre AG, Retterstol L, Stanhope R, Edge JA, McKenzie S, Lessan N,
Ghodsi M, De Rosa V, Perna F, Fontana S, Barroso I, Undlien DE, O’Rahilly
S 2007 Clinical and molecular genetic spectrum of congenital deficiency of the
leptin receptor. N Engl J Med 356:237–247
35. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ,
Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Earley AR,
Barnett AH, Prins JB, O’Rahilly S 1997 Congenital leptin deficiency is as-
sociated with severe early-onset obesity in humans. Nature 387:903–908
36. Buettner C, Pocai A, Muse ED, Etgen AM, Myers Jr MG, Rossetti L 2006
Critical role of STAT3 in leptin’s metabolic actions. Cell Metab 4:49 – 60
37. Buettner C, Muse ED, Cheng A, Chen L, Scherer T, Pocai A, Su K, Cheng B,
Li X, Harvey-White J, Schwartz GJ, Kunos G, Rossetti L, Buettner C 2008
Leptin controls adipose tissue lipogenesis via central, STAT3-independent
mechanisms. Nat Med 14:667– 675
38. Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI 1998
Leptin modulates the T-cell immune response and reverses starvation-in-
duced immunosuppression. Nature 394:897–901
39. Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ, Klein AS,
Bulkley GB, Bao C, Noble PW, Lane MD, Diehl AM 1998 Leptin regulates
proinflammatory immune responses. FASEB J 12:57– 65
40. Ingalls AM, Dickie MM, Snell GD 1950 Obese, a new mutation in the house
mouse. J Hered 41:317–318
41. Wallace AM, McMahon AD, Packard CJ, Kelly A, Shepherd J, Gaw A,
Sattar N 2001 Plasma leptin and the risk of cardiovascular disease in the
west of Scotland coronary prevention study (WOSCOPS). Circulation
104:3052–3056
42. Koh KK, Park SM, Quon MJ 2008 Leptin and cardiovascular disease: re-
sponse to therapeutic interventions. Circulation 117:3238 –3249
43. Dubey L, Hesong Z 2006 Role of leptin in atherogenesis. Exp Clin Cardol
11:269 –275
44. Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, Sanna
V, Jebb SA, Perna F, Fontana S, Lechler RI, DePaoli AM, O’Rahilly S 2002
Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neu-
roendocrine/metabolic dysfunction of human congenital leptin deficiency.
J Clin Invest 110:1093–1103
45. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM,
Hughes IA, McCamish MA, O’Rahilly S 1999 Effects of recombinant
leptin therapy in a child with congenital leptin deficiency. N Engl J Med
341:879 – 884
46. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ,
DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A 2002 Leptin-re-
placement therapy for lipodystrophy. N Engl J Med 346:570 –578
47. Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T,
Lubina JA, Patane J, Self B, Hunt P, McCamish M 1999 Recombinant leptin
for weight loss in obese and lean adults: a randomized, controlled, dose-
escalation trial. JAMA 282:1568 –1575
48. Roth JD, Roland BL, Cole RL, Trevaskis JL, Weyer C, Koda JE, Anderson
CM, Parkes DG, Baron AD 2008 Leptin responsiveness restored by amylin
agonism in diet-induced obesity: evidence from nonclinical and clinical stud-
ies. Proc Natl Acad Sci USA 105:7257–7262
49. Kern PA, Di Gregorio GB, Lu T, Rassouli N, Ranganathan G 2003 Adi-
ponectin expression from human adipose tissue: relation to obesity, insulin
resistance, and tumor necrosis factor-␣ expression. Diabetes 52:1779 –1785
50. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE,
Tataranni PA 2001 Hypoadiponectinemia in obesity and type 2 diabetes:
close association with insulin resistance and hyperinsulinemia. J Clin Endo-
crinol Metab 86:1930 –1935
51. Semple RK, Halberg NH, Burling K, Soos MA, Schraw T, Luan J, Cochran
EK, Dunger DB, Wareham NJ, Scherer PE, Gorden P, O’Rahilly S 2007
Paradoxical elevation of high-molecular weight adiponectin in acquired
extreme insulin resistance due to insulin receptor antibodies. Diabetes
56:1712–1717
52. Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, Eto K,
Yamashita T, Kamon J, Satoh H, Yano W, Froguel P, Nagai R, Kimura S,
Kadowaki T, Noda T 2002 Disruption of adiponectin causes insulin resis-
tance and neointimal formation. J Biol Chem 277:25863–25866
53. Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani
H, Furuyama N, Kondo H, Takahashi M, Arita Y, Komuro R, Ouchi N,
Kihara S, Tochino Y, Okutomi K, Horie M, Takeda S, Aoyama T, Funahashi
T, Matsuzawa Y 2002 Diet-induced insulin resistance in mice lacking adi-
ponectin/ACRP30. Nat Med 8:731–737
54. Nawrocki AR, Rajala MW, Tomas E, Pajvani UB, Saha AK, Trumbauer ME,
Pang Z, Chen AS, Ruderman NB, Chen H, Rossetti L, Scherer PE 2006 Mice
J Clin Endocrinol Metab, November 2008, 93(11):S64 –S73
lacking adiponectin show decreased hepatic insulin sensitivity and reduced
responsiveness to PPAR␥-agonists. J Biol Chem 281:2654 –2660
55. Wang Y, Lam KS, Yau MH, Xu A 2008 Post-translational modifications
of adiponectin: mechanisms and functional implications. Biochem J 409:
623– 633
56. Wang Y, Lam KS, Chan L, Chan KW, Lam JB, Lam MC, Hoo RC, Mak WW,
Cooper GJ, Xu A 2006 Post-translational modifications of the four conserved
lysine residues within the collagenous domain of adiponectin are required for
the formation of its high molecular weight oligomeric complex. J Biol Chem
281:16391–16400
57. Banga A, Bodles AM, Rasouli N, Ranganathan G, Kern PA, Owens RJ 2008
Calcium is involved in formation of high molecular weight adiponectin.
Metab Syndr Relat Disord 6:103–111
58. Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, Schulthess T, Engel J,
Brownlee M, Scherer PE 2003 Structure-function studies of the adipocyte-
secreted hormone Acrp30/adiponectin. Implications fpr metabolic regulation
and bioactivity. J Biol Chem 278:9073–9085
59. Chow WS, Cheung BM, Tso AW, Xu A, Wat NM, Fong CH, Ong LH, Tam
S, Tan KC, Janus ED, Lam TH, Lam KS 2007 Hypoadiponectinemia as a
predictor for the development of hypertension: a 5-year prospective study.
Hypertension 49:1455–1461
60. Kadowaki T, Yamauchi T 2005 Adiponectin and adiponectin receptors. En-
docr Rev 26:439 – 451
61. Heidemann C, Sun Q, van Dam RM, Meigs JB, Zhang C, Tworoger SS,
Mantzoros CS, Hu FB 2008 Total and high-molecular-weight adiponectin
and resistin in relation to the risk for type 2 diabetes in women. Ann Intern
Med 149:307–316
62. Lara-Castro C, Luo N, Wallace P, Klein RL, Garvey WT 2006 Adiponectin
multimeric complexes and the metabolic syndrome trait cluster. Diabetes
55:249 –259
63. Wang ZV, Schraw TD, Kim JY, Khan T, Rajala MW, Follenzi A, Scherer
PE 2007 Secretion of the adipocyte-specific secretory protein adiponectin
critically depends on thiol-mediated protein retention. Mol Cell Biol 27:
3716 –3731
64. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K 2006 Adi-
ponectin and adiponectin receptors in insulin resistance, diabetes, and the
metabolic syndrome. J Clin Invest 116:1784 –1792
65. Rasouli N, Yao-Borengasser A, Miles LM, Elbein SC, Kern PA 2006 In-
creased plasma adiponectin in response to pioglitazone does not result from
increased gene expression. Am J Physiol Endocrinol Metab 290:E42–E46
66. Bodles AM, Banga A, Rasouli N, Ono F, Kern PA, Owens RJ 2006 Piogli-
tazone increases secretion of high-molecular-weight adiponectin from adi-
pocytes. Am J Physiol Endocrinol Metab 291:E1100 –E1105
67. Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger JP,
Wagner JA, Wu M, Knopps A, Xiang AH, Utzschneider KM, Kahn SE, Olefsky
JM, Buchanan TA, Scherer PE 2004 Complex distribution, not absolute amount
of adiponectin, correlates with thiazolidinedione-mediated improvement in in-
sulin sensitivity. J Biol Chem 274:12152–12162
68. Rasouli N, Raue U, Miles LM, Lu T, Di Gregorio GB, Elbein SC, Kern PA
2005 Pioglitazone improves insulin sensitivity through reduction in muscle
lipid and redistribution of lipid into adipose tissue. Am J Physiol Endocrinol
Metab 288:E930 –E934
69. Zhu W, Cheng KKY, Vanhoutte PM, Lam KSL, Xu A 2008 Vascular effects
of adiponectin: molecular mechanisms and potential therapeutic interven-
tion. Clin Sci (Lond) 114:361–374
70. Kadowaki T, Yamauchi T, Kubota N 2008 The physiological and patho-
physiological role of adiponectin and adiponectin receptors in the peripheral
tissues and CNS. FEBS Lett 582:74 – 80
71. Kusminski CM, McTernan PG, Schraw T, Kos K, O’hare JP, Ahima R, Kumar
S, Scherer PE 2007 Adiponectin complexes in human cerebrospinal fluid: distinct
complex distribution from serum. Diabetologia 50:634 – 642
72. Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S, Kumagai H, Kozono H,
Takamoto I, Okamoto S, Shiuchi T, Suzuki R, Satoh H, Tsuchida A, Moroi
M, Sugi K, Noda T, Ebinuma H, Ueta Y, Kondo T, Araki E, Ezaki O, Nagai
R, Tobe K, Terauchi Y, Ueki K, Minokoshi Y, Kadowaki T 2007 Adiponectin
stimulates AMP-activated protein kinase in the hypothalamus and increases
food intake. Cell Metab 6:55– 68
73. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel
HR, Ahima RS, Lazar MA 2001 The hormone resistin links obesity to dia-
betes. Nature 409:307–312
74. Steppan CM, Brown EJ, Wright CM, Bhat S, Banerjee RR, Dai CY, Enders
GH, Silberg DG, Wen X, Wu GD, Lazar MA 2001 A family of tissue-specific
resistin-like molecules. Proc Natl Acad Sci USA 98:502–506
75. Rajala MW, Obici S, Scherer PE, Rossetti L 2003 Adipose-derived resistin and
Downloaded from jcem.endojournals.org at Universidad de Chile on January 5, 2009
jcem.endojournals.org S71
gut-derived resistin-like molecule-␤ selectively impair insulin action on glu-
cose production. J Clin Invest 111:225–230
76. Curat CA, Wegner V, Sengenes C, Miranville A, Tonus C, Busse R, Bouloumie
A 2006 Macrophages in human visceral adipose tissue: increased accumulation
in obesity and a source of resistin and visfatin. Diabetologia 49:744 –747
77. Degawa-Yamauchi M, Bovenkerk JE, Juliar BE, Watson W, Kerr K, Jones R,
Zhu Q, Considine RV 2003 Serum resistin (FIZZ3) protein is increased in
obese humans. J Clin Endocrinol Metab 88:5452–5455
78. Heilbronn LK, Rood J, Janderova L, Albu JB, Kelley DE, Ravussin E, Smith
SR 2004 Relationship between serum resistin concentrations and insulin re-
sistance in nonobese, obese, and obese diabetic subjects. J Clin Endocrinol
Metab 89:1844 –1848
79. Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R, Orlova
C, Mantzoros CS 2003 Circulating resistin levels are not associated with obesity
or insulin resistance in humans and are not regulated by fasting or leptin admin-
istration: cross-sectional and interventional studies in normal, insulin-resistant,
and diabetic subjects. J Clin Endocrinol Metab 88:4848 – 4856
80. Vozarova de Courten B, Degawa-Yamauchi M, Considine RV, Tataranni PA
2004 High serum resistin is associated with an increase in adiposity but not
a worsening of insulin resistance in Pima Indians. Diabetes [Erratum (2004)
53:2518] 53:1279 –1284
81. Hivert MF, Sullivan LM, Fox CS, Nathan DM, D’Agostino Sr RB, Wilson
PW, Meigs JB 2008 Associations of adiponectin, resistin, and tumor necrosis
factor-␣ with insulin resistance. J Clin Endocrinol Metab 93:3165–3172
82. Kamin D, Hadigan C, Lehrke M, Mazza S, Lazar MA, Grinspoon S 2005
Resistin levels in human immunodeficiency virus-infected patients with li-
poatrophy decrease in response to rosiglitazone. J Clin Endocrinol Metab
90:3423–3426
83. Abel ED, Peroni O, Kim JK, Kim YB, Boss O, Hadro E, Minnemann T,
Shulman GI, Kahn BB 2001 Adipose-selective targeting of the GLUT4 gene
impairs insulin action in muscle and liver. Nature 409:729 –733
84. Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, Kotani
K, Quadro L, Kahn BB 2005 Serum retinol binding protein 4 contributes to
insulin resistance in obesity and type 2 diabetes. Nature 436:356 –362
85. Graham TE, Yang Q, Bluher M, Hammarstedt A, Ciaraldi TP, Henry RR,
Wason CJ, Oberbach A, Jansson PA, Smith U, Kahn BB 2006 Retinol-binding
protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl
J Med 354:2552–2563
86. Lee JW, Lee HR, Shim JY, Im JA, Lee DC 21 May 2008 Abdominal visceral
fat reduction is associated with favorable changes of serum retinol binding
protein-4 in nondiabetic subjects. Endocr J [Epub ahead of print]
87. Reinehr T, Stoffel-Wagner B, Roth CL 2008 Retinol-binding protein 4 and
its relation to insulin resistance in obese children before and after weight loss.
J Clin Endocrinol Metab 93:2287–2293
88. Aeberli I, Biebinger R, Lehmann R, L’allemand D, Spinas GA, Zimmermann
MB 2007 Serum retinol-binding protein 4 concentration and its ratio to
serum retinol are associated with obesity and metabolic syndrome compo-
nents in children. J Clin Endocrinol Metab 92:4359 – 4365
89. Hahn S, Backhaus M, Broecker-Preuss M, Tan S, Dietz T, Kimmig R, Schmidt
M, Mann K, Janssen OE 2007 Retinol-binding protein 4 levels are elevated
in polycystic ovary syndrome women with obesity and impaired glucose me-
tabolism. Eur J Endocrinol 157:201–207
90. Haider DG, Schindler K, Mittermayer F, Muller M, Nowotny P, Rieger A,
Luger A, Ludvik B, Wolzt M 2007 Effect of rosiglitazone on visfatin and
retinol-binding protein-4 plasma concentrations in HIV-positive patients.
Clin Pharmacol Ther 81:580 –585
91. Jia W, Wu H, Bao Y, Wang C, Lu J, Zhu J, Xiang K 2007 Association of serum
retinol-binding protein 4 and visceral adiposity in Chinese subjects with and
without type 2 diabetes. J Clin Endocrinol Metab 92:3224 –3229
92. Kloting N, Graham TE, Berndt J, Kralisch S, Kovacs P, Wason CJ, Fasshauer
M, Schon MR, Stumvoll M, Bluher M, Kahn BB 2007 Serum retinol-binding
protein is more highly expressed in visceral than in subcutaneous adipose
tissue and is a marker of intra-abdominal fat mass. Cell Metab 6:79 – 87
93. Stefan N, Hennige AM, Staiger H, Machann J, Schick F, Schleicher E, Fritsche
A, Haring HU 2007 High circulating retinol-binding protein 4 is associated
with elevated liver fat but not with total, subcutaneous, visceral, or intramyo-
cellular fat in humans. Diabetes Care 30:1173–1178
94. Takebayashi K, Suetsugu M, Wakabayashi S, Aso Y, Inukai T 2007 Retinol
binding protein-4 levels and clinical features of type 2 diabetes patients. J Clin
Endocrinol Metab 92:2712–2719
95. Yao-Borengasser A, Varma V, Bodles AM, Rasouli N, Phanavanh B, Lee MJ,
Starks T, Kern LM, Spencer III HJ, Rashidi AA, McGehee Jr RE, Fried SK,
Kern PA 2007 Retinol binding protein 4 expression in humans: relationship
to insulin resistance, inflammation, and response to pioglitazone. J Clin En-
docrinol Metab 92:2590 –2597
S72 Rasouli and Kern Adipocytokines and Obesity
96. Janke J, Engeli S, Boschmann M, Adams F, Bohnke J, Luft FC, Sharma AM,
Jordan J 2006 Retinol-binding protein 4 in human obesity. Diabetes 55:
2805–2810
97. Hogstrom M, Nordstrom A, Nordstrom P 2008 Retinol, retinol-binding
protein 4, abdominal fat mass, peak bone mineral density, and markers of
bone metabolism in men: the Northern Osteoporosis and Obesity (NO2)
Study. Eur J Endocrinol 158:765–770
98. Ueland T, Dalsoren T, Voldner N, Godang K, Henriksen T, Bollerslev J 2008
Retinol-binding protein-4 is not strongly associated with insulin sensitivity in
normal pregnancies. Eur J Endocrinol 159:49 –54
99. von Eynatten M, Humpert PM 2008 Retinol-binding protein-4 in experi-
mental and clinical metabolic disease. Expert Rev Mol Diagn 8:289 –299
100. Gomez-Ambrosi J, Rodriguez A, Catalan V, Ramirez B, Silva C, Rotellar F,
Gil MJ, Salvador J, Fruhbeck G 2008 Serum retinol-binding protein 4 is not
increased in obesity or obesity-associated type 2 diabetes mellitus, but is
reduced after relevant reductions in body fat following gastric bypass. Clin
Endocrinol (Oxf) 69:208 –215
101. Gavi S, Qurashi S, Stuart LM, Lau R, Melendez MM, Mynarcik DC,
McNurlan MA, Gelato MC 2008 Influence of age on the association of
retinol-binding protein 4 with metabolic syndrome. Obesity (Silver
Spring) 16:893– 895
102. Hammarstedt A, Pihlajamaki J, Graham TE, Kainulainen S, Kahn BB,
Laakso M, Smith U 2008 High circulating levels of RBP4 and mRNA levels
of aP2, PGC-1␣ and UCP-2 predict improvement in insulin sensitivity fol-
lowing pioglitazone treatment of drug-naive type 2 diabetic subjects. J Intern
Med 263:440 – 449
103. Lin KD, Chang YH, Wang CL, Yang YH, Hsiao PJ, Li TH, Shin SJ 2008
Thiazolidinedione addition reduces the serum retinol-binding protein 4 in
type 2 diabetic patients treated with metformin and sulfonylurea. Transl Res
151:309 –314
104. Mody N, Graham TE, Tsuji Y, Yang Q, Kahn BB 2008 Decreased clearance
of serum retinol-binding protein and elevated levels of transthyretin in insu-
lin-resistant ob/ob mice. Am J Physiol Endocrinol Metab 294:E785–E793
105. Kitani T, Okuno S, Fujisawa H 2003 Growth phase-dependent changes in
the subcellular localization of pre-B-cell colony-enhancing factor. FEBS
Lett 544:74 –78
106. Samal B, Sun Y, Stearns G, Xie C, Suggs S, McNiece I 1994 Cloning and
characterization of the cDNA encoding a novel human pre-B-cell colony-
enhancing factor. Mol Cell Biol 14:1431–1437
107. Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K,
Matsuki Y, Murakami M, Ichisaka T, Murakami H, Watanabe E, Takagi T,
Akiyoshi M, Ohtsubo T, Kihara S, Yamashita S, Makishima M, Funahashi
T, Yamanaka S, Hiramatsu R, Matsuzawa Y, Shimomura I 2005 Visfatin: a
protein secreted by visceral fat that mimics the effects of insulin. Science
307:426 – 430
108. Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K,
Matsuki Y, Murakami M, Ichisaka T, Murakami H, Watanabe E, Takagi T,
Akiyoshi M, Ohtsubo T, Kihara S, Yamashita S, Makishima M, Funahashi
T, Yamanaka S, Hiramatsu R, Matsuzawa Y, Shimomura I 2007 Retraction.
Science 318:565
109. Revollo JR, Korner A, Mills KF, Satoh A, Wang T, Garten A, Dasgupta B,
Sasaki Y, Wolberger C, Townsend RR, Milbrandt J, Kiess W, Imai S 2007
Nampt/PBEF/visfatin regulates insulin secretion in ␤ cells as a systemic NAD
biosynthetic enzyme. Cell Metab 6:363–375
110. Berndt J, Kloting N, Kralisch S, Kovacs P, Fasshauer M, Schon MR, Stumvoll
M, Bluher M 2005 Plasma visfatin concentrations and fat depot-specific
mRNA expression in humans. Diabetes 54:2911–2916
111. Varma V, Yao-Borengasser A, Rasouli N, Bodles AM, Phanavanh B, Lee MJ,
Starks T, Kern LM, Spencer III HJ, McGehee Jr RE, Fried SK, Kern PA 2007
Human visfatin expression: relationship to insulin sensitivity, intramyocel-
lular lipid and inflammation. J Clin Endocrinol Metab 92:666 – 672
112. Chen MP, Chung FM, Chang DM, Tsai JC, Huang HF, Shin SJ, Lee YJ 2006
Elevated plasma level of visfatin/pre-B cell colony-enhancing factor in pa-
tients with type 2 diabetes mellitus. J Clin Endocrinol Metab 91:295–299
113. Hammarstedt A, Pihlajamaki J, Sopasakis VR, Gogg S, Jansson PA, Laakso
M, Smith U 2006 Visfatin is an adipokine, but it is not regulated by thiazo-
lidinediones. J Clin Endocrinol Metab 91:1181–1184
114. Haider DG, Schindler K, Schaller G, Prager G, Wolzt M, Ludvik B 2006
Increased plasma visfatin concentrations in morbidly obese subjects are re-
duced after gastric banding. J Clin Endocrinol Metab 91:1578 –1581
115. Lumeng CN, Bodzin JL, Saltiel AR 2007 Obesity induces a phenotypic switch
in adipose tissue macrophage polarization. J Clin Invest 117:175–184
116. Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-
Boris A, Poli G, Olefsky J, Karin M 2005 IKK-␤ links inflammation to obe-
sity-induced insulin resistance. Nat Med 11:191–198
Downloaded from jcem.endojournals.org at Universidad de Chile on January 5, 2009
J Clin Endocrinol Metab, November 2008, 93(11):S64 –S73
117. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS 1997 Protection
from obesity-induced insulin resistance in mice lacking TNF-␣ function. Na-
ture 389:610 – 614
118. Uysal KT, Wiesbrock SM, Hotamisligil GS 1998 Functional analysis of tu-
mor necrosis factor (TNF) receptors in TNF-␣-mediated insulin resistance in
genetic obesity. Endocrinology 139:4832– 4838
119. Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G 2001 Adipose tissue
tumor necrosis factor and interleukin-6 expression in human obesity and
insulin resistance. Am J Physiol Endocrinol Metab 280:E745–E751
120. Plomgaard P, Bouzakri K, Krogh-Madsen R, Mittendorfer B, Zierath JR,
Pedersen BK 2005 Tumor necrosis factor-␣ induces skeletal muscle insulin
resistance in healthy human subjects via inhibition of Akt substrate 160
phosphorylation. Diabetes 54:2939 –2945
121. Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R 1996 Effects of an engi-
neered human anti-TNF-␣ antibody (CDP571) on insulin sensitivity and
glycemic control in patients with NIDDM. Diabetes 45:881– 885
122. Gonzalez-Gay MA, De Matias JM, Gonzalez-Juanatey C, Garcia-Porrua C,
Sanchez-Andrade A, Martin J, Llorca J 2006 Anti-tumor necrosis factor-␣
blockade improves insulin resistance in patients with rheumatoid arthritis.
Clin Exp Rheumatol 24:83– 86
123. Seriolo B, Ferrone C, Cutolo M 2008 Longterm anti-tumor necrosis factor-␣
treatment in patients with refractory rheumatoid arthritis: relationship be-
tween insulin resistance and disease activity. J Rheumatol 35:355–357
124. Tam LS, Tomlinson B, Chu TT, Li TK, Li EK 2007 Impact of TNF inhibition
on insulin resistance and lipids levels in patients with rheumatoid arthritis.
Clin Rheumatol 26:1495–1498
125. Emanuelli B, Peraldi P, Filloux C, Sawka-Verhelle D, Hilton D, Van Obberghen
E 2000 SOCS-3 is an insulin-induced negative regulator of insulin signaling.
J Biol Chem 275:15985–15991
126. Kristiansen OP, Mandrup-Poulsen T 2005 Interleukin-6 and diabetes: the
good, the bad, or the indifferent? Diabetes 54(Suppl 2):S114 –S124
127. Ruderman NB, Keller C, Richard AM, Saha AK, Luo Z, Xiang X, Giralt M,
Ritov VB, Menshikova EV, Kelley DE, Hidalgo J, Pedersen BK, Kelly M 2006
Interleukin-6 regulation of AMP-activated protein kinase. Potential role in
the systemic response to exercise and prevention of the metabolic syndrome.
Diabetes 55(Suppl 2):S48 –S54
128. Di Gregorio GB, Hensley L, Lu T, Ranganathan G, Kern PA 2004 Lipid and
carbohydrate metabolism in mice with a targeted mutation in the IL-6 gene:
absence of development of age-related obesity. Am J Physiol Endocrinol
Metab 287:E182–E187
129. Wallenius V, Wallenius K, Ahren B, Rudling M, Carlsten H, Dickson SL,
Ohlsson C, Jansson JO 2002 Interleukin-6-deficient mice develop mature-
onset obesity. Nat Med 8:75–79
130. Sartipy P, Loskutoff DJ 2003 Monocyte chemoattractant protein 1 in obesity
and insulin resistance. Proc Natl Acad Sci USA 100:7265–7270
131. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S,
Miyachi H, Maeda S, Egashira K, Kasuga M 2006 MCP-1 contributes to
macrophage infiltration into adipose tissue, insulin resistance, and hepatic
steatosis in obesity. J Clin Invest 116:1494 –1505
132. Inouye KE, Shi H, Howard JK, Daly CH, Lord GM, Rollins BJ, Flier JS 2007
Absence of CC chemokine ligand 2 does not limit obesity-associated infil-
tration of macrophages into adipose tissue. Diabetes 56:2242–2250
133. Kiefer FW, Zeyda M, Todoric J, Huber J, Geyeregger R, Weichhart T,
Aszmann O, Ludvik B, Silberhumer GR, Prager G, Stulnig TM 2008
Osteopontin expression in human and murine obesity: extensive local
up-regulation in adipose tissue but minimal systemic alterations. Endo-
crinology 149:1350 –1357
134. Nomiyama T, Perez-Tilve D, Ogawa D, Gizard F, Zhao Y, Heywood EB,
Jones KL, Kawamori R, Cassis LA, Tschop MH, Bruemmer D 2007 Os-
teopontin mediates obesity-induced adipose tissue macrophage infiltration
and insulin resistance in mice. J Clin Invest 117:2877–2888
135. Alessi MC, Peiretti F, Morange P, Henry M, Nalbone G, Juhanvague I 1997
Production of plasminogen activator inhibitor 1 by human adipose tissue: pos-
sible link between visceral fat accumulation and vascular disease. Diabetes 46:
860 – 867
136. Cigolini M, Tonoli M, Borgato L, Frigotto L, Manzato F, Zeminian S, Cardinale
C, Camin M, Chiaramonte E, De Sandre G, Lunardi C 1999 Expression of
plasminogen activator inhibitor-1 in human adipose tissue: a role for TNF-␣?
Atherosclerosis 143:81–90
137. Alessi MC, Bastelica D, Morange P, Berthet B, Leduc I, Verdier M, Geel O,
Juhan-Vague I 2000 Plasminogen activator inhibitor 1, transforming growth
factor-␤1, and BMI are closely associated in human adipose tissue during
morbid obesity. Diabetes 49:1374 –1380
138. Mertens I, Verrijken A, Michiels JJ, Van der Planken M, Ruige JB, Van Gaal
J Clin Endocrinol Metab, November 2008, 93(11):S64 –S73
LF 2006 Among inflammation and coagulation markers, PAI-1 is a true
component of the metabolic syndrome. Int J Obes (Lond) 30:1308 –1314
139. Kanaya AM, Wassel FC, Vittinghoff E, Harris TB, Park SW, Goodpaster BH,
Tylavsky F, Cummings SR 2006 Adipocytokines and incident diabetes mel-
litus in older adults: the independent effect of plasminogen activator inhibitor
1. Arch Intern Med 166:350 –356
140. Sprengers ED, Kluft C 1987 Plasminogen activator inhibitors. Blood 69:
381–387
141. Song CZ, Siok TE, Gelehrter TD 1998 Smad4/DPC4 and Smad3 mediate
transforming growth factor-␤ (TGF-␤) signaling through direct binding to a
novel TGF-␤-responsive element in the human plasminogen activator inhib-
itor-1 promoter. J Biol Chem 273:29287–29290
142. Varma V, Yao-Borengasser A, Bodles AM, Rasouli N, Phanavanh B, Nolen
GT, Kern EM, Nagarajan R, Spencer III HJ, Lee MJ, Fried SK, McGehee Jr
Downloaded from jcem.endojournals.org at Universidad de Chile on January 5, 2009
jcem.endojournals.org S73
RE, Peterson CA, Kern PA 2008 Thrombospondin-1 is an adipokine asso-
ciated with obesity, adipose inflammation, and insulin resistance. Diabetes
57:432– 439
143. Bornstein P 2001 Thrombospondins as matricellular modulators of cell func-
tion. J Clin Invest 107:929 –934
144. Esemuede N, Lee T, Pierre-Paul D, Sumpio BE, Gahtan V 2004 The role of
thrombospondin-1 in human disease. J Surg Res 122:135–142
145. Crawford SE, Stellmach V, Murphy-Ullrich JE, Ribeiro SM, Lawler J, Hynes
RO, Boivin GP, Bouck N 1998 Thrombospondin-1 is a major activator of
TGF-␤1 in vivo. Cell 93:1159 –1170
146. Lundgren CH, Brown SL, Nordt TK, Sobel BE, Fujii S 1996 Elaboration
of type-1 plasminogen activator inhibitor from adipocytes. A potential
pathogenetic link between obesity and cardiovascular disease. Circulation
93:106 –110