Dig Dis Sci (2009) 54:1847–1856
DOI 10.1007/s10620-008-0585-3
REVIEW
Adipose Tissue: The New Endocrine Organ? A Review Article
Susan E. Wozniak Æ Laura L. Gee Æ
Mitchell S. Wachtel Æ Eldo E. Frezza
Received: 20 August 2008 / Accepted: 13 October 2008 / Published online: 4 December 2008

Springer Science+Business Media, LLC 2008
Abstract Fat is either white or brown, the latter being
found principally in neonates. White fat, which comprises
adipocytes, pre-adipocytes, macrophages, endothelial cells,
fibroblasts, and leukocytes, actively participates in hor-
monal and inflammatory systems. Adipokines include
hormones such as leptin, adiponectin, visfatin, apelin, va-
spin, hepcidine, chemerin, omentin, and inflammatory
cytokines, including tumor necrosis factor alpha (TNF),
monocyte chemoattractant protein-1 (MCP-1), and plas-
minogen activator protein (PAI). Multiple roles in
metabolic and inflammatory responses have been assigned
to adipokines; this review describes the molecular actions
and clinical significance of the more important adipokines.
The array of adipokines evidences diverse roles for adipose
tissue, which looms large in the mediators of inflammation
and metabolism. For this reason, treating obesity is more
than a reduction of excess fat; it is also the treatment of
obesity’s comorbidities, many of which will some day be
treated by drugs that counteract derangements induced by
adipokine excesses.
Keywords Adipose tissue
Resistin
Adipokines

Cytokines
Chemokines
S. E. Wozniak
L. L. Gee
E. E. Frezza
Department of Surgery, Texas Tech University Health Sciences
Center, Lubbock, TX, USA
M. S. Wachtel
Department of Pathology, Texas Tech University Health
Sciences Center, Lubbock, TX, USA
E. E. Frezza (&)
New Life Bariatric, 505 N Lake Shore Drive,
Suite 3101, Chicago, IL, USA
e-mail: eefrezza@msn.com
Introduction
The first to suggest a role beyond a repository for lipids for
adipose tissue was von Gierke, who in 1905 recognized a
role for adipose tissue in glycogen storage [1]. White adi-
pose tissue, the predominant form found in adults (brown fat
is principally found in neonates), comprises adipocytes, pre-
adipocytes, macrophages, endothelial cells, fibroblasts, and
leukocytes; its multifarious composition renders white fat an
important mediator of metabolism and inflammation [2], its
general roles being schematized in Fig. 1. Since the first
adipokine, leptin, was discovered in 1994, adipose tissue has
been granted many vital roles for the host in general, making
it an endocrine organ in its own right [3–18]. More specifi-
cally we are beginning to better understand the metabolic
and inflammatory changes that take place in chronic obesity
at the molecular level; the substratum to this discovery is the
descriptions of multiple adipokines, including adiponectin,
resistin, visfatin, apelin, vaspin, hepcidine, tumor necrosis
factor alpha (TNF), chemerin, omentin, MCP-1, and plas-
minogen activator protein (PAI), many originally described
as having originated from other than adipose tissue. Adding
to the complexity is heterogeneity with respect to body site:
the differing fat depots in the body play distinct roles,
secreting different sets of adipokines, [2, 19] as outlined in
Fig. 2. This review delineates the molecular description and
clinical significance of many of the adipokines.
Hormone-Like Adipokines
Leptin
Leptin, a 16-kDa nonglycosylated anorexia peptide, hypo-
thalamically modulates body weight, food intake, and fat
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1848 Dig Dis Sci (2009) 54:1847–1856

Fig. 1 White adipose tissue White Adipose Tissue

effects on metabolism and
inflammation. White adipose
tissue (WAT) influences
metabolism through energy
homeostasis, adipocyte
Metabolism Inflammation
differentiation, and insulin
sensitivity. WAT affects
inflammation through
inflammatory control,
cardiovascular protection, and
Cardiovascular
vascular inflammation. Figure Energy Adipocyte Insulin Inflammatory
Protection/
Vascular
adapted from Juge-Aubry et al. Homeostasis Differentiation Sensitivity Control Inflammation
Neo-angiogenesis
[2]

- IL-1 -Adiponectin
IL-1Ra -IL-1
-TNFa -IL-6 -IL-1Ra
-IL8
-Leptin -MCP-1 -IL-1 -IL-8 -IL-10
-IL-10
- IL-6 -IL-1 -IL-1Ra -IL-9 -VEGF
-MCP-1
-IL-1 -IL-1Ra -IL-6 -IP-10 -Leptin
-RANTES
-IL-1Ra IL-6 -TNFa -TNFa -TNFa
-Resistin
-MCP-1
-PAI
-RANTES

Fig. 2 Local effects of white Main Categories of Specialized

adipose tissue secretion. Local Functions of Local
WAT Deposits
subgroups of white adipose
tissue (WAT) include visceral,
muscle, epicardial, perivascular,
and kidney. Visceral WAT
controls local and systemic
inflammation while epicardial Visceral Muscle Epicardial Perivascular Kidney
WAT controls local
inflammation and chemotaxis.
Muscle WAT is mainly
involved in insulin resistance
and kidney WAT affects Secretion of:
IL-1/IL-1Ra
intravascular volume Secretion of: Secretion of: IL-6
Secretion of:
hypertension. Perivascular IL-8
TNFa
IL-6 IL-8
IP-10 IL-1b IP-10 Reabsorption of Na+
WAT is largely involved with MCP-1
Free Fatty Acids
TNFa MCP-1
atherosclerosis and IL-6
RANTES MCP-1 TNFa
hypertension. Figure adapted RANTES
from Juge-Aubry et al. [2]

Atherosclerosis
Local and Systemic Local Inflammation Increased Intravascular
Insulin Resistance and Systolic
Inflammation and Chemotaxis Volume Hypertension
Hypertension

stores [4, 5]. Leptin levels are proportional to insulin levels
and inversely proportional to glucocorticoid concentrations
[3–5]. Inflammatory cytokines, including TNF, interleukin-1
(IL-1), and leukemia inhibitory factor, induce leptin pro-
duction [6]. Testicular steroids decrease and ovarian steroids
increase leptin concentrations [7, 8]. Leptin regulates pan-
creatic islet cells, growth hormone levels, immunology
homeostasis, hematopoiesis, angiogenesis, wound healing,
osteogenesis, and gastrointestinal function [3, 9]. In the brain
leptin has been shown to influence the cortex, hippocampus,
and hypothalamus, exerting in the latter local control over
appetite and levels of sex steroids, thyroxin, and growth
hormone [10–13]. Leptin administration can regulate pub-
erty in adults and children adults [17]. Decreased leptin
signaling or receptor function increased energy intake and
lowers energy expenditure [15], with leptin deficiency itself
being a known cause of severe early-onset obesity, hypo-
gonadism, hyperinsulinemia, hyperphagia, and impaired T-
cell-mediated immunity, treatable with recombinant leptin
[16, 17]. High levels of leptin in obese patients do not effect
appetite suppression because of resistance to the hormone,
which has been posited to be due to leptin receptor signaling
defects, downstream blockade in neuronal circuits, and
defects in leptin transport across the blood–brain barrier [18].

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Resistin
Resistin is a 12-kDa peptide that mostly circulates as a
high-molecular-weight hexamer but also has a distinct,
more active low-molecular-weight complex [20]. The
hormone is expressed in greatest concentration in mono-
nuclear cells, but is also seen in muscle, pancreatic cells,
and adipocytes [21]. Resistin encoding messenger RNA
(mRNA) displays an even wider range, having been found
in white fat, spleen, hypothalamus, adrenal gland, skeletal
muscle, gastrointestinal tract, and pancreas [21]. The
adipokine stimulates inflammatory cytokines such as IL-1,
IL-6, and IL-12 and TNF through a nuclear factor kappa B
(NF-j-B)-dependent pathway [22–24] and also reduces
endothelial cell production of intercellular adhesion mol-
ecule-1 (ICAM-1), vascular cell-adhesion molecule-1
(VCAM-1), and CC chemokine ligand-2 (CCL-2) [25].
Resistin has been accorded a diabetogenic role in mice, but
its function in the pathogenesis of human diabetes remains
a matter of debate, with no definite role assigned to it with
respect to insulin resistance, its name notwithstanding [26,
27]. Atherosclerotic aneurysmal vessel wall macrophages
secrete resistin [28]. Chronic kidney disease increases
resistin levels [29]. The hormone accumulates in the
synovial lining of rheumatoid arthritis patients [21].
Adiponectin
The gene for adiponectin, is located at chromosomal band
3q27, a susceptibility locus for diabetes and cardiovascular
disease [30]. Adiponectin has both an adaptor protein,
APPL1, as well as two receptors, AdipoR1 and AdipoR2,
each comprising seven transmembrane domains [31].
AdipoR1 and AdipoR2 are the main adiponectin receptors
with respect to glucose and lipid metabolism [32]. Current
experiments also suggest a molecule known as T-cadherin
to be an adiponectin receptor [33]. The protein, found in
both murine and human blood [34], accounts for 0.01% of
human plasma protein; its concentration markedly declines
with morbid obesity [35, 36]. Adiponectin induces endo-
thelial VCAM-1, ICAM-1, and pentraxin-3 expression [2].
The hormone, by decreasing reactive oxygen, is an anti-
oxidant [37]. Adiponectin augments endothelial nitrous
oxide production, acting to protect the vasculature by
reduced platelet aggregation and vasodilation [38, 39].
Adiponectin itself may be antiatherosclerotic, as it acts as
an endogenous antithrombotic factor [39, 40] and inhibits
macrophage activation and foam cell accumulation, both
being critical cytologic elements of atheromas [41]. Stroke,
coronary heart disease, steatohepatitis, insulin resistance,
nonalcoholic fatty liver disease, and a wide array of can-
cers have been associated with decreased adiponectin
levels [42]. Hypoadiponectinemia has been correlated with
1849
increased atherosclerosis-related compounds, including
adipocyte fatty-acid-binding protein (A-FABP), lipocalin-
2, as well as other markers of oxidative stress [43, 44]. The
compound has great potential as a marker for atheroscle-
rotic disease, its decrease having been shown to be
predictive of acute coronary syndrome, myocardial
infarction, coronary artery disease, and ischemic cerebro-
vascular disease [45, 46].
Apelin
Apelin, produced by adipocytes, vascular stromal cells, and
the heart, increases with increased insulin levels and also
with obesity [47]. Cardiac apelin levels are downregulated
by angiotensin II and restored with angiotensin type 1
receptor blocker in animal models with heart failure [48].
Ischemic cardiomyopathy [49] and hypoxia [50] increase
apelin levels; atrial fibrillation and chronic heart failure
have been associated with decreased apelin levels [51].
Apelin has positive hemodynamic effect, having been
shown to be an inotrope in normal and failing rat hearts and
in isolated cardiomyocytes [52]. Apelin may regulate
insulin resistance by facilitating expression of brown adi-
pose tissue uncoupling proteins and altering adiponectin
levels [53].
Visfatin, Hepcidine, Omentin, Vaspin, Adipsin,
and Angiopoietin
Less well described, but probably equally important, other
compounds have been discovered to be products of white
fat. Visfatin, also produced by lymphocytes, decreases
insulin resistance [54]. Visfatin inhibits apoptosis of acti-
vated neutrophils [55], implicating it both as a cause of
damage in such conditions as acute lung injury [56] and as a
potential therapeutic agent in sepsis [55]. Visfatin admin-
istration to mice decreases blood glucose levels; mice
lacking one allele have increased plasma glucose [54].
Levels of hepcidine, which was first described as a urinary
antimicrobial peptide, increase with obesity and correlate
with levels of C-reactive protein and IL-6 [57, 58]. Hepci-
dine regulates iron homeostasis by inhibiting iron release
from macrophages, iron absorption by enterocytes, and iron
transport across the placenta. Omentin levels decrease with
obesity and insulin resistance and increase as high-density
lipoprotein and adiponectin increase [59]. Chemerin levels
increase with increases in body mass index (BMI), blood
pressure, and triglycerides; chemerin receptor defects
impair 3T3-L1 cell differentiation into adipocytes and
decrease adiponectin and leptin expression [60]. Vaspin, a
serine protease inhibitor, reduces levels of leptin, resistin,
and TNF; it improves insulin sensitivity and shows
decreased concentrations in the physically fit and increased
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concentrations in obese patients, especially those with
impaired glucose tolerance [61, 62]. Adipsin, also known as
complement factor D, is mainly produced by monocytes
and macrophages resident in fat [63, 64]; it mediates the
rate-limiting step in the complement activation alternative
pathway and, some say, generates an acylation stimulating
protein that increases adipocyte triglyceride production
[63]. Serum retinol-binding protein, heretofore limited to
the delivery of retinol, has been shown to be increased in
diabetic patients and glucose transporter-4 (GLUT-4)-defi-
cient mice, a condition that is reversed by fenretinide, which
increases urinary excretion of the protein, yielding, for
mice, decreased insulin resistance [65]. Angiopoietin-like
peptide-4, induced by peroxisome proliferator-activated
receptor (PPAR)-a in the liver and PPAR-c in adipose tis-
sue, shows levels that correlate with lipoprotein [66];
because its injection yields increased triglyceride levels and
because other similar proteins are resident in the liver and
the gut, the protein may well be part of a signaling pathway
that regulates lipid metabolism and storage [66–68].
Inflammatory Cytokines and Anti-Inflammatory
Factors
Cytokines
The more than 100 inflammatory cytokines, divided as
shown in Fig. 3 into interferons, interleukins, hematopoi-
etic factors, chemokines, and growth factors, influence
AdipocyteSecreted Factors
Inflammatory Cytokines
Adipocytokine Interferons Interleukins Growth Factors
Leptin IFNb IL-1 TNFa
Resistin IFNy IL-6
Visfatin
Adiponectin
Fig. 3 Inflammatory and anti-inflammatory adipocyte-secreted fac-
tors. Inflammatory cytokine subgroups include adipocytokines,
interferons, interleukins, growth factors, and chemokines. Anti-
inflammatory factors include anti-inflammatory cytokines, receptor
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Dig Dis Sci (2009) 54:1847–1856
growth, immunity, inflammation, apoptosis, and cell divi-
sion [69]. Their bioactivity is such that only 10% of the
receptors need to be engaged to elicit a response [70, 71].
TNF, IL-1, and IL-6, which can initiate both acute and
chronic inflammation, are controlled by three classes of
proteins: soluble receptors that prevent binding to the cell
surface, competitive binding proteins, such as IL-1Ra, and
anti-inflammatory cytokines, such as IL-4, IL-10, or TGF-
b, which decrease inflammatory cytokine production [70].
TNF increases production of itself and of IL-6, nerve
growth factor, MCP-1, resistin and visfatin [72, 73],
decreases adiponectin and leptin concentrations [72, 73],
and facilitates endothelial dysfunction and atherogenesis
[74]. PAI increases when insulin resistance develops,
encourages thrombosis when local increases are present,
particularly atheromas of type II diabetic patients [75], and
has been posited to bear a relationship with adiponectin
with respect to cardiovascular disease [76]. Adipocyte
differentiation is increased with decreased PAI and
increased adiponectin and resistin [77].
Chemokines
Chemokines, traditionally seen as regulators of chemotaxis
of inflammatory cells, are now known to be important
mediators of a wide array of phenomena, including lym-
phoid organ development, rheumatoid arthritis, and
atherosclerosis. Chemokines act locally, meaning that one
can see chemokine activity in perivascular fat in cardio-
vascular disease, subcutaneous fat in inflammatory skin
Anti-inflammatory
Factors
Chemokines Anti-inflammatory Receptor antagonist: Soluble Receptors Adipocytokine
Cytokines
IL-8
IP-10 IL-4 IL-1Ra IL-1RII Adiponectin
RANTES IL-10 sTNFR
MCP-1 TGFb sIL-1R
antagonists, soluble receptors, and adipocytokines. Many of the newly
discovered adipose-tissue-secreted factors were not added to this
figure due to a lack of research classifying them as inflammatory or
anti-inflammatory. Figure adapted from Juge-Aubry et al. [2]
Dig Dis Sci (2009) 54:1847–1856 1851

Adipocytokine

anti-inflammatory inflammatory

adiponectin
leptin resistin visfatin

Endothelial adhesion
IL-6 (C68) Apoptosis of
TNF (B:35) Molecules (VCAM1 &
neutrophils (B98)
ROS (B70) ICAM1) B88
Phagocytosis (B42)
IL-8 (C119)
TNF (B68, 71) IL-12 (C86)
NF-κΒ (B40,41,43)
IL-6 (C119)
Chemotaxis (B70) IL-6 (C86)
IFNγ (B42)
innate
IL-12 (C68) IL-1β (B86)
Endothelial adhesion
molecules (B40) NK-cell function (B72) NF-κB (B87)

IL-6 (C42.) Neutrophil activation TNF (B86,87)

(CD11b) B70
IL-1RA (B42)

IL-10 (C42.)

TH2 response (IL-4) B64

T-cell proliferation (B 64)

T-cell responses (B42)
Thymocytesurvival (B73)
B-cell lymphopoiesis ND ND ND

adaptive
(B117) Lymphopoiesis (B73)

TH1 response
(IL-2 and IFNγ) B64

Fig. 4 Adipocytokine role in adaptive and innate immunity. This is a
more specific version of Fig. 3 focusing on adiponectin, leptin,
resistin, and visfatin. Adiponectin primarily has anti-inflammatory
properties, which become inflammatory in the presence of lipop-
olysaccaride. Adiponectin’s anti-inflammatory properties are part of
both innate and adaptive immunity. Leptin, resistin, and visfatin are
only known to have inflammatory properties. Leptin’s inflammatory
properties are part of both innate and adaptive immunity while
resistin’s and visfatin’s inflammatory properties have only been
shown to play a part in innate immunity. Figure adapted from Tilg
et al. [86]

diseases, and perirenal fat in glomerulonephritis [78]. Discussion

Chemokines produced by fat, including IL-8, MCP-1,
interferon-gamma inducible protein 10 (IP-10), and regu-
lated upon activation normal T-cell express sequence
(RANTES) are often regulated by hormone-like adipo-
kines, including leptin [79]. MCP-1, a mediator of T-
lymphocyte recruiting and monocyte trafficking, is
increased by leptin, obesity, and insulin-resistance-induc-
ing hormones [80]. Epicardial fat produces more MCP-1
than does subcutaneous fat [81]; there exists a MCP-1
polymorphism associated with high coronary atheroscle-
rosis risk [82].
Adipose tissue plays a major role with respect to metabo-
lism and inflammation, a role whose mediators comprise
adipokines, which include hormone-like proteins and
inflammatory cytokines. The locations in which adipose
tissue reside help determine its role. Whereas visceral
adipose tissue can influence both systemic and local
inflammatory processes, muscular deposits figure more
prominently with respect to insulin resistance, perivascular
fat can facilitate the development of atheromas, and peri-
renal fat can contribute to hypertension via increased

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1852 Dig Dis Sci (2009) 54:1847–1856

lean obese

blood vessel

apoptotic
cell
adipose
adipose
tissue
tissue macrophages
(AT)
(AT)

macrophages
adipocytes
adipocytes

Liver
insulin
resistance
Adiponectin
+

Liver
+
CRP
Adiponectin Leptin + ΙL-6 Resistin/

TNFα FIZZ3

Leptin

? Inflammation

?
TNFα
IL-6 ?
+

Resistin/FIZZ3
Arteries +
Anti- Muscle Liver (Atherosclerosis)
?
atherogenic Insulin responsiveness
responsiveness Muscle
insulin
resistance

Fig. 5 Adipokine expression in lean and obese individuals. On the
left side of the figure the lean individual has regular-sized adipocytes
and healthy levels of macrophages in their adipose tissue (AT), while
on the right side the obese individual has enlarged adipocytes, with
many more undergoing apoptosis and large amounts of macrophages
engulfing these apoptotic cells. In the lean individual high levels of
adiponectin and low levels of leptin and resistin maintain a healthy
homeostatic equilibrium with antiatherogenic properties, and muscle
and liver responsiveness. In contrast, in the obese individual on the
right, adiponectin levels are low and resistin and visfatin levels are
high. This difference furthers atherosclerosis and muscle and liver
insulin resistance. Figure adapted from Bastard et al. [87]

intravascular volume. The same adipokine, moreover, can
have diverse effects: on a local basis, IL-6 both disrupts
insulin signaling in hepatocytes and fat cells and regulates
intramyocardial lipid accumulation to the degree that it
serves as a cardioprotective agent; systemically it has been
assigned a role in the pathogenesis of diabetes mellitus [80,
83–87].
Although the factors have been divided for convenience
into hormone-like and inflammatory cytokine adipokines,
the latter being divided into inflammatory and anti-
inflammatory (Fig. 3), it should be clear that the boundary
between the two categories is quite porous, with inflam-
matory cytokines influencing hormone-like proteins and
vice versa.
As the interaction of leptin and resistin with IL-6 and
TNF shows (Fig. 5), the presence of obesity alters the
relationship of the adipokines. The left side of Fig. 5, from
a lean patient, shows adipose tissue with normal-sized

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adipocytes and only occasional macrophages. In lean
patients, adiponectin concentrations are high and resistin
concentrations are low; high levels of adiponectin exert
antiatherogenic properties and increase insulin respon-
siveness, unimpeded by high resistin levels. The right side,
from an obese patient, shows large adipocytes, more
macrophages, and more apoptotic adipocytes; the cell
necrosis induces inflammation and has been related to
insulin resistance.
Obese persons have high levels of leptin and resistin,
yielding increased TNF and IL-6, which have been related
to atherosclerosis via C-reactive protein. In contrast the
obese patient on the right side of Fig. 5 has high leptin and
resistin levels and low adiponectin levels. The high leptin
and resistin levels increase insulin resistance and augment
production of TNF and IL-6 whereby they can cause ath-
erosclerosis through liver C-reactive protein. The low level
of adiponectin in obese persons signifies the deprivation of
a compound that counteracts the negative effects of high
leptin and resistin.
One of the issues still in question is if diabetes type II
and other metabolic syndrome pathology are secondary to
an inflammatory reaction. Some suggestions can be
hypothesized:
1. Lipid elevation and accumulation in nonadipose
tissues (from chronic overnutrition and/or leptin defi-
ciency or resistance)
2. Insulin resistance
3. Uncertainties:
• Cardiovascular disease (CVD) risk factors cluster
but may not be a syndrome
• Insulin resistance as unifying etiology not proven
• Macrophages may play major role
The issues of macrophage and inflammatory factors
creating an insulin resistance (IR) environment can be
summarized in the following points:
1. IR present in chronic pro-inflammatory state
2. Inflammatory factors are present in target organs and
appear to be increased in adipose tissue of obese
humans
3. Increased insulin sensitivity in macrophage-specific
IKKb knock-out mouse
From our review, it appears that not only is there a
correlation between metabolic and anti-inflammatory fac-
tors and type II diabetes, but also that most of the
inflammatory factors are not produced in the ‘‘far distance’’
area of the body but in situ by the ‘‘fat cell.’’ This has
opened a new door in research to understand the reaction
and metabolic response of the adipocytes, which can open
the possibility of understanding different disease and not
1853
just type II diabetes. This research will open the door to the
neuroendocrine inflammatory theory of the diabetic.
Conclusion
Knowledge of this relationship has generated research,
delineated herein, into clinical manipulations with respect
to adiponectin that might benefit the obese. Although
exponentially increasing knowledge of adipokines prom-
ises much with respect to therapy, it markedly diminishes
the possibility of summarizing adipokine function in a
single review. Future reviews on adipocyte literature will
likely focus on specific roles of adipose tissue, perhaps
even being limited to specific roles of a few adipokines in
specific adipose tissue deposits.
References
1. Von Gierke E. Ueber Fett Metabolism. Der Deutsch Ges Path.
1906;10:182–185.
2. Juge-Aubry CE, Henrichot E, Meier CA. Adipose tissue a regu-
lator of inflammation. Best Pract Res Clin Endocrinol Metab.
2005;19(4):547–566. doi:10.1016/j.beem.2005.07.009.
3. Fantuzzi G, Faggioni R. Leptin in the regulation of immunity,
inflammation, and hematopoiesis. J Leukoc Biol. 2000;68:
437–446.
4. Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler
RI. Leptin modulates the T-cell immune response and reverses
starvation-induced immunosuppression. Nature. 1998;394:897–
901. doi:10.1038/29795.
5. Ge H, Huang L, Pourbahrami T, Li C. Generation of soluble
leptin receptor by ectodomain shedding of membrane-spanning
receptors in vitro and in vivo. J Biol Chem. 2002;277:45898–
45903. doi:10.1074/jbc.M205825200.
6. Gualillo O, Eira S, Lago F, Diéguez C, Casanueva FF. Elevated
serum leptin concentrations induced by experimental acute
inflammation. Life Sci. 2000;67:2433–2441. doi:10.1016/S0024-
3205(00)00827-4.
7. Blum WF, Englaro P, Hatsch S, et al. Plasma leptin levels in
healthy children and adolescents: dependence on BMI, body fat
mass, gender, pubertal stage, and testosterone. Clin Endocrinol
Metab. 1997;82:2904–2910. doi:10.1210/jc.82.9.2904.
8. Castracane VD, Kraemer RR, Franken MA, Kraemer GR, Gimpel
T. Serum leptin concentration in women: effect of age, obesity,
and estrogen administration. Fertil Steril. 1998;70:472–477. doi:
10.1016/S0015-0282(98)00187-3.
9. Ashwin PJ, Dilipbhai PJ. Leptin and the cardiovascular system: a
review. Recent Pat Cardiovasc Drug Discov. 2007;2:100–109.
10. Irving AJ, Wallace L, Durakoglugil D, Harvey J. Leptin enhances
NR2B-mediated N-methyl-D-aspartate responses via a mitogen-
activated protein kinase-dependent process in cerebellar granule
cells. Neuroscience. 2006;138(4):1137–1148. doi:10.1016/j.neuro
science.2005.11.042.
11. Inui A. Feeding and body-weight regulation by hypothalamic
neuropeptides-mediation of the actions of leptin. Trends Neuro-
sci. 1999;22:62–67. doi:10.1016/S0166-2236(98)01292-2.
12. Huo L, Müzberg H, Nillni EA, Bjorbaek C. Role of signal
transducer and activator of transcription 3 in regulation of
123
1854
hypothalamic trh gene expression by leptin. Endocrinology.
2004;145:2516–2523. doi:10.1210/en.2003-1242.
13. Elmquist JK, Ahima RS, Maratos-Flier E, Flier JS, Saper CB.
Leptin activates neurons in ventrobasal hypothalamus and
brainstem. Endocrinology. 1997;138:839–842. doi:10.1210/en.
138.2.839.
14. Green B. Lamotrigine in mood disorders. Curr Med Res Opin.
2003;19:272–277. doi:10.1185/030079903125001703.
15. Friedman JM, Halaas JL. Leptin and the regulation of body
weight in mammals. Nature. 1998;395:763–770. doi:10.1038/
27376.
16. Farooqi IS, Matarese G, Lord GM, et al. Beneficial effects of
leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/
metabolic dysfunction of human congenital leptin deficiency. J
Clin Invest. 2002;110:1093–1103.
17. Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin
missense mutation associated with hypogonadism and morbid
obesity. Nat Genet. 1998;18:213–215. doi:10.1038/ng0398-213.
18. Flier JS. Obesity wars: molecular progress confronts an
expanding epidemic. Cell. 2004;116:337–350. doi:10.1016/
S0092-8674(03)01081-X.
19. Gesta S, Tseng YH, Kahn CR. Developmental origin of fat:
tracking obesity to its source. Cell. 2007;131(2):242–256. 19.
20. Patel SD, Rajala MW, Rossetti L, Scherer PE, Shapiro L. Disulfide-
dependent multimeric assembly of resistin family hormones. Sci-
ence. 2004;304:1154–1158. doi:10.1126/science.1093466.
21. Kusminski CM, McTernan PG, Kumar S. Role of resistin in
obesity, insulin resistance and type II diabetes. Clin Sci.
2005;109:243–256. doi:10.1042/CS20050078.
22. Kaser S, Kaser A, Sandhofer A, Ebenbichler CF, Tilg H, Patsch
JR. Resistin messenger-RNA expression is increased by proin-
flammatory cytokines in vitro. Biochem Biophys Res Commun.
2003;309:286–290. doi:10.1016/j.bbrc.2003.07.003.
23. Silswal N, Singh AK, Aruna B, Mukhopadhyay S, Ghosh S,
Ehtesham NZ. Human resistin stimulates the pro-inflammatory
cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB-
dependent pathway. Biochem Biophys Res Commun. 2005;334:
1092–1101. doi:10.1016/j.bbrc.2005.06.202.
24. Bokarewa M, Nagaev I, Dahlberg L, Smith U, Tarkowski A.
Resistin, an adipokine with potent proinflammatory properties. J
Immunol. 2005;174:5789–5795.
25. Verma S, Li SH, Wang CH, et al. Resistin promotes endothelial
cell activation: further evidence of adipokine-endothelial inter-
action. Circulation. 2003;108:736–740. doi:10.1161/01.CIR.000
0084503.91330.49.
26. Savage DB, Sewter CP, Klenk ES, et al. Resistin/Fizz3 expres-
sion in relation to obesity and peroxisome proliferator-activated
receptor-gamma action in humans. Diabetes. 2001;50:2199–
2202. doi:10.2337/diabetes.50.10.2199.
27. Utzschneider KM, Carr DB, Tong J, et al. Resistin is not asso-
ciated with insulin sensitivity or the metabolic syndrome in
humans. Diabetologia. 2005;48:2330–2333. doi:10.1007/s00125-
005-1932-y.
28. Jung HS, Park KH, Cho YM, et al. Resistin is secreted from
macrophages in atheromas and promotes atherosclerosis. Cardio-
vasc Res. 2006;69:76–85. doi:10.1016/j.cardiores.2005.09.015.
29. Axelsson J, Bergsten A, Qureshi AR, et al. Elevated resistin levels
in chronic kidney disease are associated with decreased glomerular
filtration rate and inflammation, but not with insulin resistance.
Kidney Int. 2006;69:596–604. doi:10.1038/sj.ki.5000089.
30. Saito K, Tobe T, Minoshima S, et al. Organization of the gene for
gelatin-binding protein. Gene. 1999;229:67–73. doi:10.1016/
S0378-1119(99)00041-4.
31. Mao X, Kikani CK, Riojas RA, et al. APPL1 binds to adiponectin
receptors and mediates adiponectin receptors and mediates
123
Dig Dis Sci (2009) 54:1847–1856
adiponectin signalling and function. Nat Cell Biol. 2006;8:516–
523. doi:10.1038/ncb1404.
32. Bjursell M, Ahnmark A, Bohlooly YM, et al. Opposing effects of
adiponectin receptors 1 and 2 on energy metabolism. Diabetes.
2007;65:583–593. doi:10.2337/db06-1432.
33. Hug C, Wang J, Ahmad NS, Bogan JS, Tsao TS, Lodish HF. T-
cadherin is a receptor for hexameric and high-molecular-weight
forms of Acrp30/adiponectin. Proc Natl Acad Sci USA. 2004;101:
10308–10313. doi:10.1073/pnas.0403382101.
34. Menzaghi C, Trischitta V, Doria A. Genetic influences of adipo-
nectin on insulin resistance, Type II diabetes and cardiovascular
disease. Diabetes. 2007;56:1198–1209. doi:10.2337/db06-0506.
35. Xu A, Tso AW, Cheung BM, et al. Circulating adipocyte-fatty
acid binding proteinr levels predicts the development of the
metabolic syndrome: a 5-year prospective study. Circulation.
2007;115:1537–1543. doi:10.1161/CIRCULATIONAHA.106.
647503.
36. Arita Y, Kihara S, Ouchi N, et al. Paradoxical decrease of an
adipose-specific proteirn, adiponectin, in obesity. Biochem Bio-
phys Res Commun. 1999;257:167–175. doi:10.1006/bbrc.1999.
0255.
37. Ouedraogo R, Wu X, Xu SQ, et al. Adiponectin suppression of
high-glucose-induced reactive oxygen species in vascular endo-
thelial cells: evidence for involvement of a cAMP signaling
pathway. Diabetes. 2006;55(6):1840–1846. doi:10.2337/db05-
1174.
38. Matsuo Y, Imanishi T, Kuroi A, et al. Effects of plasma adipo-
nectin levels on the number and function of endothelial
progenitor cells in patients with coronary artery disease. Circ J.
2007;71:1376–1382. doi:10.1253/circj.71.1376.
39. Ouchi N, Kobayashi H, Kihara S, et al. Adiponectin stimulates
angiogenesis by promothing cross-talk between AMP-activated
protein kinase and Akt signaling in endothelial cells. J Biol
Chem. 2003;279:1304–1309. doi:10.1074/jbc.M310389200.
40. Kato H, Kashiwagi H, Shiraga M, et al. Adiponectin acts as an
endogenous antithrombotic factor. Arterioscler Thromb Vasc Biol.
2006;26:224–230. doi:10.1161/01.ATV.0000194076.84568.81.
41. Wang Y, Lam KS, Xu JY, et al. Adiponectin inhibits cell pro-
liferation by interacting with several growth factors in an
oligomerization-dependent manner. J Biol Chem. 2005;280:
18341–18347. doi:10.1074/jbc.M501149200.
42. Trujillo ME, Scherer PE. Adiponectin: journey from an adipocyte
secretory protein to biomarker of the metabolic syndrome. J
Intern Med. 2005;257:167–175. doi:10.1111/j.1365-2796.2004.
01426.x.
43. Xu A, Chan KW, Hoo RL, et al. Testosterone selectively reduces
the high molecular weight form of adiponectin by inhibiting its
secretion from adipocytes. J Biol Chem. 2005;280:18073–18080.
doi:10.1074/jbc.M414231200.
44. Maturese G, Mantxoros C, La Cava A. Leptin and adipocyto-
kines: bridging the gap between immunity and atherosclerosis.
Curr Pharm Des. 2007;13:3676–3680. doi:10.2174/1381612077
83018635.
45. Kiris I, Tekin I, Yesildag A, et al. Inverse relationship between
adiponectin levels and subclinical carotid athersclerosis in
patients undergoing coronary artery bypass grafting. Int Heart J.
2006;47:855–866. doi:10.1536/ihj.47.855.
46. Szmitko PE, Teoh H, Stewart DJ, Verma S. Adiponectin and
cardiovascular disease: state of the art? Am J Physiol Heart Circ
Physiol. 2007;292:H1655–H1663. doi:10.1152/ajpheart.01072.
2006.
47. Lee DK, George SR, O’Dowd B. Unraveling the roles of the
apelin system: prospective therapeutic applications in heart fail-
ure and obesity. Trends Pharmacol Sci. 2006;27:190–194. doi:
10.1016/j.tips.2006.02.006.
Dig Dis Sci (2009) 54:1847–1856
48. Iwanaga Y, Kihara Y, Takenaka H, Kita T. Down-regulation of
cardiac apelin system in hypertrophied and failing hearts: possi-
ble role of angiotensin II-angiotensin type 1 receptor system. J
Mol Cell Cardiol. 2006;41:798–806. doi:10.1016/j.yjmcc.2006.
07.004.
49. Atluri P, Morine KJ, Liao GP, et al. Ischemic heart failure
enhances endogenous myocardial apelin and APJ receptor
expression. Cell Mol Biol Lett. 2007;12:127–138. doi:10.2478/
s11658-006-0058-7.
50. Ronkainen VP, Ronkainen JJ, Hánninen SL, et al. Hypoxia inducible
factor regulates the cardiac expression and secretion of apelin.
FASEB J. 2007;21:1821–1830. doi:10.1096/fj.06-7294com.
51. Chong KS, Gardner RS, Morton JJ, Ashley EA, McDonagh TA.
Plasma concentrations of the novel peptide apelin are decreased
in patients with chronic heart failure. Eur J Heart Fail.
2006;8:355–360. doi:10.1016/j.ejheart.2005.10.007.
52. Grisk O. Apelin and vascular dysfunction in Type II diabetes.
Cardiovasc Res. 2007;74:339–340. doi:10.1016/j.cardiores.2007.
03.026.
53. Higuchi K, Masaki T, Goth K, et al. Apelin, an APJ receptor
ligand, regulates body adiposity and favors the messenger ribo-
nucleic acid expression of uncoupling proteins in mice.
Endocrinology. 2007;148:2690–2697. doi:10.1210/en.2006-1270.
54. Fukuhara A, Matsuda M, Nishizawa M, et al. Visfatin: a protein
secreted by visceral fat that mimics the effects of insulin. Science.
2005;307:426–430. doi:10.1126/science.1097243.
55. Jia S, Li Y, Parodo J, et al. Pre-B cell colony-enhancing factor
inhibits neutrophil apoptosis in experimental inflammation and
clinical sepsis. J Clin Invest. 2004;113:1318–1327.
56. Ye SQ, Simon BA, Maloney JP, et al. Pre-B-cell colony-
enhancing factor as a potential novel biomarker in acute lung
injury. Am J Respir Crit Care Med. 2005;171:361–370. doi:
10.1164/rccm.200404-563OC.
57. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin a urinary
antimicrobial peptide synthesized in the liver. J Biol Chem.
2001;276:7806–7810. doi:10.1074/jbc.M008922200.
58. Bekri S, Gual P, Anty R, et al. Increased adipose tissue expres-
sion of hepcidin in severe obesity is independent from diabetes
and NASH. Gastroenterology. 2006;131(3):788–796. doi:
10.1053/j.gastro.2006.07.007.
59. De Souza CM, Yang RZ, Lee MJ, et al. Omentin plasma levels
and gene expression are decreased in obesity. Diabetes.
2007;56:1655–1661. doi:10.2337/db06-1506.
60. Bozaoglu K, Bolton K, McMillan J, et al. Chemerin is a novel
adipokine associated with obesity and metabolic syndrome.
Endocrinology. 2007;148:4687–4694. doi:10.1210/en.2007-0175.
61. Hida K, Wada J, Eguchi J, et al. Visceral adipose tissue-derived
serine protease inhibitor: a unique insulin-sensitizing adipocyto-
kine in obesity. Proc Natl Acad Sci USA. 2005;102:10610–10615.
doi:10.1073/pnas.0504703102.
62. Youn BS, Klöting N, Kratzsch J, Lee N, Park JW. Serum vaspin
concentrations in human obesity and type 2 diabetes. Diabetes.
2008;57(2):372–377. doi:10.2337/db07-1045.
63. White RT, Damm D, Hancock N, et al. Human adipsin is iden-
tical to complement factor D and is expressed at high levels in
adipose tissue. J Biol Chem. 1992;267:9210–9213.
64. Gabrielsson BG, Johansson JM, Lonn M, et al. High expression
of complement components in omental adipose tissue in obese
men. Obes Res. 2003;11:699–708. doi:10.1038/oby.2003.100.
65. Yang Q, Graham TE, Mody N, et al. Serum retinol binding
protein 4 contributes to insulin resistance in obesity and Type II
diabetes. Nature. 2005;436:356–362.
66. Mandard S, Zandbergen F, van Straten E, et al. The fasting-induced
adipose factor/angiopoietin-like protein 4 is physically associated
with lipoproteins and governs plasm lipid levels and adiposity.
J Biol Chem. 2006;281:934–944. doi:10.1074/jbc.M506519200.
1855
67. Mandard S, Zandbergen F, Tan NS, et al. The direct peroxisome
proliferator-activated receptor target fasting-induced adipose
factor (FIAF/PGAR/ANGPTL4) is present in blood plasma as a
truncated protein that is increased by fenofibrate treatment. J Biol
Chem. 2004;279:34411–34420. doi:10.1074/jbc.M403058200.
68. Wang Y, Lam KS, Lam JB, et al. Overexpression of Angio-
poietin-like protein 4 alters mitochondria activities and modulates
methionine metabolic cycle in the liver tissues of db/db diabetic
mice. Mol Endocrinol. 2007;21:972–986. doi:10.1210/me.2006-
0249.
69. Debrunner M, Schuiki E, Minder E, et al. Proinflammatory
cytokines in acute myocardial infarction with and without car-
diogenic shock. Clin Res Cardiol. 2008;97:298–305. doi:
10.1007/s00392-007-0626-5.
70. Hansson GK. Inflammation, atherosclerosis, and coronary artery
disease. N Engl J Med. 2005;352:1685–1695. doi:10.1056/
NEJMra043430.
71. Oppenheim JJ, Feldmann M. Introduction to the role of cytokines
in innate host defense and adaptative immunity. Elsevier;
2001:3–20.
72. Wang B, Trayhurn P. Acute and prolonged effects of TNF-alpha
on the expression and secretion of inflammation-related adipo-
kines by human adipocytes differentiated in culture. Pflugers
Arch. 2006;452:418–427. doi:10.1007/s00424-006-0055-8.
73. Hector J, Schwarzloh B, Goehring J, et al. TNF-alpha alters
visfatin and adiponectin levels in human fat. Horm Metab Res.
2007;39:250–255. doi:10.1055/s-2007-973075.
74. Mateo T, Naim Abu Nabh Y, Losada M, et al. A critical role for
TNF-alpha in the selective attachment of mononuclear leukocytes
to angiotensin-II-stimulated arterioles. Blood. 2007;110:1895–
1902. doi:10.1182/blood-2007-01-070607.
75. Aso Y. Plasminogen activator inhibitor in vascular inflammation
and thrombosis. Front Biosci. 2007;12:2957–2966. doi:10.2741/
2285.
76. Maruyoshi H, Kojima S, Funahashi T, et al. Adiponectin is
inversely related to plasminogen activator inhibitor type 1 in
patients with stable exertional angina. Thromb Haemost.
2004;91:1026–1030.
77. Liang X, Kanjanabuch T, Mao SL, et al. Plasminogen activator
inhibitor-1 modulates adipocyte differentiation. Am J Physiol
Endocrinol Metab. 2006;290:E103–E113. doi:10.1152/ajpendo.
00605.2004.
78. Montani JP, Carroll JF, Dwyer TM, Antic V, Yang Z, Dulloo AG.
Ectopic fat storage in heart, blood vessels and kidneys in the
pathogenesis of cardiovascular diseases. Int J Obes. 2004;28:
S58–S65. doi:10.1038/sj.ijo.0802858.
79. Laing KJ, Secombes CJ. Chemokines. Dev Comp Immunol.
2004;28:443–460. doi:10.1016/j.dci.2003.09.006.
80. Kralisch S, Bluher M, Paschke R, Stumvoll M, Fasshauer M.
Adipokines and adipocyte targets in the future management of
obesity and the metabolic syndrome. Mini Rev Med Chem.
2007;7:39–45. doi:10.2174/138955707779317821.
81. Mazurek T, Zhang L, Zalewski A, et al. Human epicardial adipose
tissue is a source of inflammatory mediators. Circulation.
2003;108:2460–2466. doi:10.1161/01.CIR.0000099542.57313.C5.
82. Kim MP, Wahl LM, Yanek LR, Becker DM, Becker LC. A
monocyte chemoattractant protein-1 gene polymorphism is
associated with occult ischemia in a high-risk asymptomatic
population. Atherosclerosis. 2007;192:366–372. doi:10.1016/
j.atherosclerosis.2006.06.029.
83. Chabowski A, Zmijewska M, Gorski J, Bonen A, Kamiński K,
Winnicka MM. Effect of IL-6 deficiency on myocardial expres-
sion of fatty acid transporters and intracellular lipid deposits.
J Physiol Pharmacol. 2007;58:73–82.
84. Smart N, Mojet MH, Latchman DS, Marber MS, Duchen MR,
Heads RJ. IL-6 induces PI3-kinase and nitric oxide-dependent
123
1856
protection and preserves mitochondrial function in cardiomyo-
cytes. Cardiovasc Res. 2006;69:164–177. doi:10.1016/j.cardiores.
2005.08.017.
85. Nishida M, Moriyama Y, Ishii K, et al. Effects of IL-6, adipo-
nectin, CRP and metabolic syndrome on subclinical
atherosclerosis. Clin Chim Acta. 2007;384:99–104. doi:10.1016/
j.cca.2007.06.009.
123
Dig Dis Sci (2009) 54:1847–1856
86. Tilg H, Moschen AR. Adipocytokines: mediators linking adipose
tissue, inflammation and immunity. Nat Rev Immunol. 2006;6:
772–783.
87. Bastard JP, Maachi M, Lagathu C, Kim MJ, Caron M. Recent
advances in the relationship between obesity, inflammation and
insulin resistance. Eur Cytokine Netw. 2006;17:4–12.