Documentos de Académico
Documentos de Profesional
Documentos de Cultura
Abstract | There has been much effort recently to define the role of adipocytokines, which
are soluble mediators derived mainly from adipocytes (fat cells), in the interaction between
adipose tissue, inflammation and immunity. The adipocytokines adiponectin and leptin have
emerged as the most abundant adipocyte products, thereby redefining adipose tissue as a
key component not only of the endocrine system, but also of the immune system. Indeed,
as we discuss here, several adipocytokines have a central role in the regulation of insulin
resistance, as well as many aspects of inflammation and immunity. Other adipocytokines,
such as visfatin, have only recently been identified. Understanding this rapidly growing family
of mainly adipocyte-derived mediators might be of importance in the development of new
therapies for obesity-associated diseases.
Atherosclerosis
A chronic disorder of the
arterial wall characterized
by endothelial damage that
gradually induces deposits
of cholesterol, cellular debris,
calcium and other substances.
These deposits finally lead to
plaque formation and arterial
stiffness.
www.nature.com/reviews/immunol
2006 Nature Publishing Group
REVIEWS
Weight gain
Lean adipose tissue
Adipocyte
Blood
vessel
Macrophage
Apoptotic
adipocyte
Crosstalk
Adipocytokines
Adiponectin
Leptin
Resistin
Macrophagederived factors
Resistin (human)
IL-1
Complement factors
Complement factors are
components of the
complement system. Activation
of these factors, which involves
proteolytic cleavage of serum
and cell-surface glycoproteins,
leads to the formation of a
terminal cell-lytic complex
inside the cell membrane of a
target cell. Complement
fragments such as C3a and
C5a have important proinflammatory properties, such
as vasodilation, chemotaxis
and opsonization.
REVIEWS
Box 1 | Insulin resistance, obesity and inflammation
Insulin regulates the uptake, oxidation and storage of fuel in insulin-sensitive tissues,
such as the liver, skeletal muscle and adipose tissue, and also macrophages. Obesity,
in particular visceral obesity, which is the accumulation of adipose tissue inside the
abdominal cavity, is associated with resistance to the effects of insulin (insulin
resistance) on peripheral glucose and fatty-acid utilization, often leading to type 2
diabetes mellitus. With the recent trend for individuals to be more obese, a large
increase in the prevalence of insulin resistance in westernized countries is expected.
Insulin resistance, together with the associated hyperinsulinaemia and hyperglycaemia,
and the presence of pro-inflammatory mediators might lead to a state of vascular
endothelial dysfunction, an abnormal lipid profile, hypertension and vascular
inflammation, all of which promote the development of atherosclerotic cardiovascular
disease.
Subclinical, low-grade inflammation might have an important role in the pathogenesis
of insulin resistance and type 2 diabetes mellitus. Population studies show a strong
correlation between the levels of pro-inflammatory biomarkers, such as C-reactive
protein, interleukin-6 and tumour-necrosis factor, and perturbations in glucose
homeostasis, obesity and atherosclerosis. However, although epidemiological
correlations have been established, the exact cellular and molecular mechanisms that
link obesity and insulin resistance are unknown. Insulin resistance might be partly
precipitated or accelerated by an acute-phase reaction as part of the innate immune
response, in which large amounts of pro-inflammatory mediators and insufficient
amounts of anti-inflammatory mediators, such as adiponectin, are released from
adipose tissue.
ob/ob mice
Mice with a spontaneous
mutation in the gene encoding
leptin (chromosome 6) that
leads to decreased leptin
production. These mice are
severely obese and develop
noninsulin-dependent diabetes
mellitus.
Endoplasmic-reticulum
stress
(ER stress). A response by the
ER that results in the disruption
of protein folding and in the
accumulation of unfolded
proteins in the ER.
Adiponectin
Although adiponectin is synthesized mainly by adipocytes, it is also expressed by skeletal muscle cells, cardiac myocytes and endothelial cells2123 (FIG. 2a). It has
sequence homology with a family of proteins that are
characterized by an amino-terminal collagen-like region
and a carboxy-terminal, complement factor C1q-like
globular domain2426. Adiponectin exists as a full-length
protein, as well as a proteolytic cleavage fragment,
consisting of the globular C-terminal domain (which
is known as globular adiponectin). It is thought that
a leukocyte elastase, secreted by activated monocytes
and/or neutrophils, mediates this cleavage process
and generates the globular fragment of adiponectin.
Globular adiponection can trimerize after cleavage, but
cannot oligomerize further27. Full-length adiponectin
can exist as: a trimer (known as low-molecular-weight
adiponectin); a hexamer, which consists of two trimers
linked by a disulphide bond (known as middle-molecularweight adiponectin); and a high-molecular-weight
12- to 18-mer (FIG. 2a). Adiponectin circulates at high
concentrations in human serum (510 mg per ml,
compared with leptin, which circulates at a concentration of a few ng per ml) and it has a wide range of
biological activities9. Serum levels of adiponectin are
markedly decreased in individuals with visceral obesity
and states of insulin resistance, such as non-alcoholic
fatty liver disease, atherosclerosis and type 2 diabetes
mellitus, and adiponectin levels correlate inversely with
insulin resistance28. Both trimers and other oligomers
of adiponectin are present in the circulation, whereas
the presence of the globular fragment in the serum in
humans has been questioned29,30. It has been suggested
recently that the ratio, and not the absolute amounts, of
high-molecular-weight and low-molecular-weight adiponectin in the serum might be crucial in determining
insulin sensitivity31. In support of the importance of circulating high-molecular-weight adiponectin in protecting
against insulin resistance, moderate weight loss leads to a
relative increase in the ratio of high-molecular-weight to
middle-molecular-weight adiponectin and a decrease
in the amount of low-molecular-weight adiponectin in
the serum32.
Two receptors for adiponectin have been identified recently (ADIPOR1 and ADIPOR2). ADIPOR1 is
expressed widely in mice, whereas ADIPOR2 is expressed
mainly in the liver33. Whereas globular adiponectin seems
to activate mainly ADIPOR1, ADIPOR2 engages mainly
with the full-length variant of adiponectin33. In addition,
T-cadherin, which is expressed by many cells including
endothelial cells and smooth muscle cells, seems to function as a receptor for middle-molecular-weight and highmolecular-weight adiponectin, but not for the trimeric
(low-molecular-weight) and globular forms34.
TNF suppresses the transcription of adiponectin in
an adipocyte cell line, which might explain the lower
levels of serum adiponectin in individuals who are
www.nature.com/reviews/immunol
2006 Nature Publishing Group
REVIEWS
a
Adipocyte
Skeletal and
cardiac myocytes
Endothelial cell
Low-molecularweight adiponectin
Globular
adiponectin
Globular
adiponectin
Middle-molecularweight adiponectin
High-molecularweight adiponectin
Low-molecularweight adiponectin
ADIPOR1
ADIPOR2
TNFR1
AMPK
IKK
IKK IKK
IB
p50 p65
NF-B
Metabolic function
of AMPK
-oxidation
GLUT4 translocation
ACC (Malonyl-CoA)
SREBP1C
Immunological
function of
adiponectin
TNF
IFN
IL-10
IL-1RA
PPAR
PPRE
p50 p65
NF-B-binding motif
Figure 2 | Adiponectin: sources, structure and effects on pro- and antiinflammatory cytokines. a | Adiponectin is produced mainly by adipocytes, but other
cell types, such as skeletal and cardiac myocytes and endothelial cells, can also produce
this adipocytokine. Adiponectin exists as a full-length trimer (low-molecular-weight
form), as well as a proteolytic cleavage fragment (globular adiponectin). The full-length
trimer can dimerize to form a hexamer (middle-molecular-weight form), which can then
oligomerize to form a polymer (high-molecular-weight form). It has been proposed that
cleavage of full-length adiponectin by a leukocyte elastase secreted by activated
monocytes and/or neutrophils generates the globular fragment. b | Adiponectin
interacts with at least two known cellular receptors (ADIPOR1 and ADIPOR2). Activation
of ADIPOR1 and/or ADIPOR2 by adiponectin stimulates the activation of peroxisomeproliferator-activated receptor- (PPAR), AMP-activated protein kinase (AMPK) and
p38 mitogen-activated protein kinase33. Adiponectin regulates the expression of several
pro- and anti-inflammatory cytokines. Its main anti-inflammatory function might be
related to its capacity to suppress the synthesis of tumour-necrosis factor (TNF) and
interferon- (IFN) and to induce the production of anti-inflammatory cytokines such as
interleukin-10 (IL-10) and IL-1 receptor antagonist (IL-1RA). Activation of PPARs exerts
anti-inflammatory effects through inhibition of the transcriptional activation of proinflammatory response genes. ACC, acetyl-CoA carboxylase; GLUT4, glucose transporter
type 4; IKK, inhibitor of nuclear factor-B (IB) kinase; NF-B, nuclear factor-B;
PPRE, peroxisome-proliferator response element; SREBP1C, sterol-regulatoryelement-binding protein 1C; TNFR, TNF receptor.
REVIEWS
a Adiponectin
Monocyte
Globular
adiponectin
Apoptosis
LPS
ADIPOR1
CD14
Phagocytosis
TLR4
Macrophage
TNF
IFN
Microorganism
IB
p50 p65
NF-B
PPAR
IL-10
IL-1RA
PPRE
b Leptin
Monocyte
Activation
Proliferation
Migration
Leptin
Phagocytosis
OBRb
Macrophage
Microorganism
NOS2
ROS
ERK
p38
STAT3
TNF
IL-6
IL-12
c Resistin
Monocyte
?
Resistin
LPS
Unknown
receptor
CD14
TLR4
Phagocytosis
Macrophage
p38
ERK
Microorganism
PI3K
TNF
IL-1
IL-6
IL-12
NF-B-binding motif
p50 p65
www.nature.com/reviews/immunol
2006 Nature Publishing Group
REVIEWS
Table 1 | Effects of adipocytokines on the immune system and linked diseases
Adipocytokine
Inflammatory effect
Effects on immunity
Associated diseases
Innate
Adaptive
Adiponectin
Anti-inflammatory
Endothelial adhesion
molecules40
NF-B40,41,43
TNF35
IL-6(REF. 42)
IFN 42
IL-10 (REF. 42)
IL-1RA42
Phagocytosis42
B-cell lymphopoiesis117
T-cell responses42
Pro-inflammatory
CXCL8 in presence of
LPS44
ND
Leptin
Pro-inflammatory
TNF68,71
IL-6 (REF. 68)
IL-12 (REF. 68)
Neutrophil activation
(CD11b)70
ROS70
Chemotaxis70
NK-cell function72
Lymphopoiesis73
Thymocyte survival73
T-cell proliferation64
TH1 response
(IL-2 and IFN)64
TH2 response (IL-4)64
Insulin resistance9
Experimentally induced hepatitis
(ConA)75,76
EAE and antigen-induced arthritis4,77
Experimentally induced colitis:
CD4+CD45RBhi T-cell transfer78; and IL-10deficient mice113
Asthma110
Cancer104
Resistin
Pro-inflammatory
TNF86,87
IL-186
IL-6 (REF. 86)
IL-12 (REF. 86)
NF-B87
Endothelial adhesion
molecules (VCAM1 and
ICAM1)88
ND
Visfatin
ND
ND
CCl4, carbon tetrachloride; ConA, concanavalin A; CXCL, CXC-chemokine ligand; EAE, experimental autoimmune encephalomyelitis; ICAM, intercellular adhesion
molecule; IFN, interferon-; IL, interleukin; IL-1RA, IL-1 receptor antagonist; LPS, lipopolysaccharide; ND, not determined; NF-B, nuclear factor-B; NK, natural
killer; ROS, reactive oxygen species; TH, T helper; TNF, tumour-necrosis factor; VCAM, vascular cell-adhesion molecule.
Collagen-like region
The amino-terminal domain
of adiponectin contains a signal
sequence that is followed by
a stretch of 22 collagen-like
repeats, consisting of 7 perfect
Gly-X-Pro repeats and
15 imperfect Gly-X-Y repeats
(where X and Y are different
amino acids), which similar
to procollagen allows the
assembly of three full-length
adiponectin molecules to an
adiponectin trimer.
The liver is one of the main insulin-sensitive tissues and insulin resistance has an important role in
the development of non-alcoholic fatty liver disease.
Therefore, several studies have assessed the roles of
fat, inflammation and adiponectin in experimental
liver disease. Adiponectin has anti-inflammatory
effects in various animal models of liver inflammation.
Administration of adiponectin has beneficial effects in
both alcoholic and non-alcoholic fatty liver disease
in mice, by suppressing the expression of TNF in the
liver. Adiponectin also decreases hepatomegaly, steatosis and the levels of liver enzymes49. In addition, adiponectin attenuates liver fibrosis in the carbon-tetrachloride
liver-fibrosis model50 and protects against endotoxininduced liver injury in another model of fatty-liver
disease, the KK-Ay obese mouse model51. Sennello and
colleagues studied concanavalin A (ConA)-induced
hepatotoxicity in lipodystrophic transgenic mice (which
constitutively express a truncated form of SREBP1c and
lack virtually all white adipose tissue) and lean, wildtype control mice52. Serum adiponectin levels were low
in lipodystrophic mice compared with controls, and the
REVIEWS
Visceral obesity
Accumulation of adipose tissue
inside the abdominal cavity,
in particular at omental and
mesenteric regions, which are
drained by the portal vein and
therefore have direct access
to the liver.
T-cadherin
A member of the cadherin
family of transmembrane
glycoproteins that mediate
cell-adhesive interactions.
Peroxisome-proliferatoractivated receptor-
(PPAR). A nuclear receptor
that is a master transcriptional
regulator of metabolism and
fat-cell formation. The activity
of PPAR can be modulated
by the direct binding of
small molecules
thiazolidinediones. PPAR has
anti-inflammatory properties
by limiting the availability of
limited cofactors or blocking
promoters of pro-inflammatory
genes.
Carbon-tetrachloride
liver-fibrosis model
Intraperitoneal or oral
administration of hepatotoxic
carbon tetrachloride (CCl4)
to mice is a commonly used
model of both acute and
chronic liver injury. CCl4 causes
hepatocyte injury that is
characterized by centrilobular
necrosis followed by hepatic
fibrosis.
Leptin
The role of leptin in modulating the immune response
and inflammation has become increasingly evident and
has been reviewed recently4. In addition to regulating
neuroendocrine function, energy homeostasis, haematopoiesis and angiogenesis, this adipocytokine is an
important mediator of immune-mediated diseases and
inflammatory processes4.
Similar to adiponectin, leptin is produced mainly
by adipocytes. However, unlike adiponectin, leptin is
considered to be a pro-inflammatory cytokine and it
has structural similarity to other pro-inflammatory
cytokines such as IL-6, IL-12 and granulocyte colonystimulating factor. The main function of leptin is control of appetite4. Indeed, mice with a mutation in the
gene encoding leptin (ob/ob mice) or the gene encoding
the leptin receptor (db/db mice) have obese phenotypes
and are used in many studies as mouse models of obesity. However, these mice also have various defects in
cell-mediated and humoral immunity6264.
Serum levels of leptin reflect the amount of energy
stored in the adipose tissue and are proportional to
overall adipose mass in both mice and humans4,65.
Serum levels are 23 times higher in women than in
men, even when adjusted for age and body-mass index
(BMI). In animal models, expression of leptin is
increased in conditions that are associated with the
release of pro-inflammatory cytokines, as induced
during acute inflammatory conditions such as sepsis66,67. An increase in leptin levels and a decrease in
expression of mRNA encoding the full-length isoform
b receptor (OBR b, which is one of at least six alternatively spliced isoforms, each of which has a cytoplasmic domain of a different length) has been observed in
diet-induced obese rats4. In addition to adipose tissue,
leptin is produced by several other tissues, including
placenta, bone marrow, stomach, muscle and perhaps
the brain4. Therefore, pro-inflammatory mediators
and obesity seem to be the main factors responsible
for increased leptin synthesis.
Role in innate and adaptive immunity. In monocytes
and macrophages, leptin increases the production of
pro-inflammatory cytokines such as TNF, IL-6 and
IL-12 (REF. 68) (FIG. 3b). It also upregulates the expression of pro-inflammatory and pro-angiogenic factors,
such as CCL2 and vascular endothelial growth factor,
respectively, in human hepatic stellate cells69. This effect
in human stellate cells is mediated through activation of
NF-B, as well as other signalling intermediates, including the serine/threonine protein kinase AKT, which is
the main downstream target of phosphatidylinositol
3-kinase69. Leptin also activates neutrophils, as assessed
by increased expression of CD11b, and stimulates the
proliferation of human circulating monocytes in vitro
and upregulates the expression of activation markers
such as CD25 (also known as IL-2R) and CD71 (the
transferrin receptor) on these cells9,70. Leptin-induced
TNF production by murine peritoneal macrophages is
inhibited by globular adiponectin through suppression
of the phosphorylation of extracellular-signal-regulated
kinase 1 (ERK1), ERK2 and p38 (REF. 71). Furthermore,
leptin stimulates neutrophil chemotaxis and the production of reactive oxygen species (ROS) by these cells, and
regulates natural killer (NK)-cell differentiation, proliferation, activation and cytotoxicity72. Most of these
pro-inflammatory effects are mediated through the long
isoform of the leptin receptor (OBRb), which is expressed
mainly by endothelial cells and various leukocytes.
The effects of leptin on adaptive immunity have been
well studied4 (FIG. 4). Leptin induces the proliferation of
naive CD4+CD45RA+ T cells, but inhibits the proliferation
of memory CD4+CD45RO+ T cells in a mixed lymphocyte
reaction (MLR)64. In T-cell proliferation assays with
mouse cells, leptin increased production of the T helper
1 (TH1) cytokines IL-2 and IFN, and suppressed production of the TH2 cytokine IL-4 (REF. 64). Administration of
leptin reversed the immunosuppressive effects of acute
starvation in mice64 and provided a survival signal for
thymocytes, thereby protecting the mice from starvationinduced lymphoid atrophy. Leptin has also been shown
to increase thymic cellularity in ob/ob mice73. Despite this
evidence of a role for leptin in immune responses in vitro
and in mouse models, it is currently unclear whether
leptin influences immune responses in humans.
Role in inflammation. The role of leptin in inflammation is incompletely understood. Endogenous leptin
protects against TNF-mediated toxicity. Ob/ob mice and
www.nature.com/reviews/immunol
2006 Nature Publishing Group
REVIEWS
Thymic homeostasis
Apoptosis
CD4+CD8+ T cells
Thymocyte number CD4+CD8 T cells
T-cell proliferation
Adiponectin
TH1 cytokines
TNF
IFN
IL-10
B-cell lymphopoiesis
B-cell number
COX1/COX2 and
PGE2 in stromal cells
Lipodystrophic transgenic
mice
Transgenic mice that express a
truncated, constitutively active
form of the sterol-regulatoryelement-binding protein 1C
(SREBP1C) transcription factor
under the control of the
adipose-specific aP2 promoter.
Lipodystrophic mice have
low plasma leptin levels,
hyperphagia, hyperglycaemia
and hyperinsulinaemia.
Body-mass index
(BMI). This is the most
frequently used method to
gauge an individuals deviation
from normal body weight.
The BMI is the quotient of
body weight (in kg) through
the square of height (m).
Underweight: <20; ideal:
2025; overweight: >25;
obese: >30.
TNF-mediated toxicity
The injection of tumournecrosis factor (TNF) into
animals, which results in acute
anorexia, weight loss, shock
and even death.
Experimental autoimmune
encephalomyelitis
(EAE). An experimental model
of multiple sclerosis that is
induced by immunization
of susceptible animals with
myelin-derived antigens,
such as myelin basic protein,
proteolipid protein or myelin
oligodendrocyte glycoprotein.
Leptin
TH2 cytokines
IL-4
IgG2a switch
Resistin
The adipocytokine resistin was discovered by three
independent groups 7981. Resistin (also known as
FIZZ3), which is a 114-amino-acid polypeptide, was
originally shown to induce insulin resistance in mice80.
It belongs to a family of cysteine-rich proteins, also
known as resistin-like molecules (RELMs), that have
been implicated in the regulation of inflammatory
processes79. Resistin was shown to circulate in two distinct forms: a more prevalent high-molecular-weight
hexamer and a substantially more bioactive, but less
prevalent, low-molecular-weight complex82.
mRNA encoding resistin can be found in mice and
humans in various tissues, including adipose tissue, the
hypothalamus, adrenal gland, spleen, skeletal muscle,
pancreas and gastrointestinal tract5. Although resistin protein synthesis in mice seems to be restricted to
adipocytes, in humans, adipocytes, muscle, pancreatic
cells and mononuclear cells such as macrophages can
synthesize this protein. Expression levels of the gene
encoding resistin have been shown to be higher in
human peripheral-blood mononuclear cells (PBMCs)
than in adipocytes; however, comparative protein data
are not available5. So, it still remains to be shown which
cell type in humans is mainly responsible for systemic
production and for the high circulating levels of resistin.
Remarkably, at the protein level, human resistin is only
55% identical to its mouse counterpart, which indicates
that it might not be evolutionarily well conserved across
species.
In human PBMCs, expression of resistin mRNA is
markedly increased by the pro-inflammatory cytokines
IL-1, IL-6 and TNF, and by LPS, whereas IFN and
leptin had no effect83. Similarly, stimulation of human
macrophages with LPS led to increased resistin mRNA
expression, and administration of LPS to humans
resulted in a marked increase in the level of resistin in
the serum84. The induction of resistin synthesis can be
VOLUME 6 | O CTOBER 2006 | 779
REVIEWS
attenuated by PPAR agonists5,84. Accordingly, treatment
of patients with type 2 diabetes mellitus with the PPAR
agonist pioglitazone decreased serum levels of resistin85.
In addition, several factors such as pituitary, steroid
and thyroid hormones, adrenaline, 3-adrenoreceptor
activation, endothelin-1 and insulin modulate resistin
expression5,84.
Role in immunity. Resistin strongly upregulates the
expression of TNF and IL-6 by human PBMCs and
induces arthritis after injection into the joints of
healthy mice86. These pro-inflammatory properties
of resistin were abrogated by an NF-B inhibitor,
showing the important role of NF-B in resistincontrolled inflammatory reactions. Resistin has also been
shown to accumulate in the inflamed joints of patients
with rheumatoid arthritis and its levels correlate with
markers of inflammation5. Human resistin stimulates
synthesis of the pro-inflammatory cytokines TNF, IL-1,
IL-6 and IL-12 by various cell types through an NF-Bdependent pathway83,87 (FIG. 3c). In further support of
its pro-inflammatory profile, resistin also upregulates
the expression of vascular cell-adhesion molecule 1
(VCAM1), intercellular adhesion molecule 1 (ICAM1)
and CCL2 by human endothelial cells and induces these
cells to release endothelin-1 (REF. 88).
Role in inflammation and insulin resistance. Resistin
has been implicated in the pathogenesis of obesityassociated insulin resistance and type 2 diabetes mellitus
in mouse models80, whereas such a role in humans is
still debated8991. Although a clear function for resistin in
humans is still lacking, its pro-inflammatory properties
indicate that it has a role in inflammatory processes5.
Macrophages infiltrating human atherosclerotic aneurysms
secrete resistin92. Resistin and adiponectin have reciprocal
effects on vascular endothelial cells: resistin induces the
expression of VCAM1, ICAM1 and pentraxin-3, whereas
adiponectin downregulates the expression of these molecules93. Increased levels of resistin in chronic kidney
disease are associated with impaired renal function and
inflammation, but not with insulin resistance94.
Therefore, this adipocytokine, at least in humans, has
many features of a pro-inflammatory cytokine and could
have a role in inflammatory diseases with or without
associated insulin resistance. These pro-inflammatory
effects, however, are based on a small number of studies
and much more information is required to characterize
resistin more fully in both mice and humans.
Atherosclerotic aneurysm
A localized dilation of a blood
vessel by more than 50%
of its diameter owing to
atherosclerotic structural
damage of the vessel wall.
www.nature.com/reviews/immunol
2006 Nature Publishing Group
REVIEWS
levels of circulating adiponectin105108. Another study
indicated an association of obesity and decreased adiponectin serum concentrations with colorectal adenomas and a higher risk of colorectal cancer109. Although
these first studies are only descriptive and do not allow
further conclusions to be drawn, adipocytokines could
be attractive candidates as the missing link between
obesity and cancer.
An association between obesity and increased
asthma incidence and severity has been reported in
some studies3. Administration of leptin increases airway hyperresponsivness and the production of TH2
cytokines in ovalbumin-sensitized mice110. High leptin
levels have been observed in asthmatic children compared with a control group with similar BMI, indicating that in addition to BMI, other factors might affect
leptin levels in these patients9. However, the association
of obesity with asthma in this study might also be influenced by other factors, such as the increased prevalence
of gastro-oesophageal reflux disease observed in the
obese population.
Overexpression of adipocytokines, including adiponectin, leptin and resistin, in the mesenteric adipose
tissue of patients with Crohns disease after ileocoecal
surgical resection has been reported 111. In Crohns
disease, leptin and adiponectin are highly expressed in
the mesenteric fat tissue, indicating that both pro- and
anti-inflammatory adipocytokines are overexpressed in
this type of inflammation111,112. Leptin-deficient mice
are protected from inflammation in some experimental models of inflammatory bowel disease113. However,
there is no clear association between obesity and the
development of inflammatory bowel disease, although
obesity has been associated with increased disease
severity114.
1.
Conclusions
Great strides have been made towards understanding
the molecules linking obesity, inflammation and immunity and understanding why obesity leads to chronic
inflammation. It is now evident that there are prototypic
adipocytokines, such as adiponectin and leptin, that are
synthesized mainly in the fat tissue, circulate at high
concentrations (in particular, adiponectin), function in a
hormone-like manner and have many of the features of
classical cytokines. These two mediators have dominated
the field of adipocytokine research recently and there is
increasing evidence that they are involved in many diseases
and, under certain circumstances, might crossregulate
each other.
Other adipocytokines, such as resistin and visfatin,
are also produced by adipocytes but an important site of
synthesis might be outside the adipose tissue, in particular by monocytes and macrophages. Resistin, although
differing in several functions between mice and humans,
seems to be mainly a pro-inflammatory mediator. Other
adipocytokines, such as VASPIN and RBP4, have only
recently been identified. Understanding the mechanisms that lead from obesity to inflammation will have
important implications for the design of new therapies to
reduce the morbidity and mortality of obesity.
REVIEWS
29. Waki, H. et al. Impaired multimerization of human
adiponectin mutants associated with diabetes.
Molecular structure and multimer formation of
adiponectin. J. Biol. Chem. 278, 4035240363
(2003).
30. Fisher, F. F. et al. Serum high molecular weight
complex of adiponectin correlates better with glucose
tolerance than total serum adiponectin in Indo-Asian
males. Diabetologia 48, 10841087 (2005).
31. Pajvani, U. B. et al. Complex distribution, not absolute
amount of adiponectin, correlates with
thiazolidinedione-mediated improvement in insulin
sensitivity. J. Biol. Chem. 279, 1215212162 (2004).
32. Bobbert, T. et al. Changes of adiponectin oligomer
composition by moderate weight reduction. Diabetes
54, 27122719 (2005).
33. Yamauchi, T. et al. Cloning of adiponectin receptors
that mediate antidiabetic metabolic effects. Nature
423, 762769 (2003).
This is the first report of the isolation and
characterization of adiponectin receptors 1 and 2.
34. Hug, C. et al. T-cadherin is a receptor for
hexameric and high-molecular-weight forms of
Acrp30/adiponectin. Proc. Natl Acad. Sci. USA
101, 1030810313 (2004).
35. Maeda, N. et al. Diet-induced insulin resistance
in mice lacking adiponectin/ACRP30. Nature Med.
8, 731737 (2002).
36. Fasshauer, M. et al. Adiponectin gene expression
and secretion is inhibited by interleukin-6 in 3T3-L1
adipocytes. Biochem. Biophys. Res. Commun.
301, 10451050 (2003).
37. Bruun, J. M. et al. Regulation of adiponectin by
adipose tissue-derived cytokines: in vivo and in vitro
investigations in humans. Am. J. Physiol. Endocrinol.
Metab. 285, E527-E533 (2003).
38. Maeda, N. et al. PPAR ligands increase expression
and plasma concentrations of adiponectin, an
adipose-derived protein. Diabetes 50, 20942099
(2001).
39. Iwaki, M. et al. Induction of adiponectin, a fat-derived
antidiabetic and antiatherogenic factor, by nuclear
receptors. Diabetes 52, 16551663 (2003).
40. Ouchi, N. et al. Novel modulator for endothelial
adhesion molecules: adipocyte-derived plasma protein
adiponectin. Circulation 100, 24732476 (1999).
41. Yokota, T. et al. Adiponectin, a new member of the
family of soluble defense collagens, negatively regulates
the growth of myelomonocytic progenitors and the
functions of macrophages. Blood 96, 17231732
(2000).
42. Wolf, A. M., Wolf, D., Rumpold, H., Enrich, B. & Tilg, H.
Adiponectin induces the anti-inflammatory cytokines
IL-10 and IL-1RA in human leukocytes. Biochem.
Biophys. Res. Commun. 323, 630635 (2004).
43. Yamaguchi, N. et al. Adiponectin inhibits Toll-like
receptor family-induced signaling. FEBS Lett.
579, 68216826 (2005).
44. Saijo, S., Nagata, K., Nakano, Y., Tobe, T. &
Kobayashi, Y. Inhibition by adiponectin of IL-8
production by human macrophages upon coculturing
with late apoptotic cells. Biochem. Biophys. Res.
Commun. 334, 11801183 (2005).
45. Neumeier, M. et al. Different effects of adiponectin
isoforms in human monocytic cells. J. Leukocyte Biol.
79, 803808 (2006).
46. Berg, A. H., Combs, T. P. & Scherer, P. E. ACRP30/
adiponectin: an adipokine regulating glucose and lipid
metabolism. Trends Endocrinol. Metab. 13, 8489
(2002).
47. Nawrocki, A. R. et al. Mice lacking adiponectin show
decreased hepatic insulin sensitivity and reduced
responsiveness to peroxisome proliferator-activated
receptor- agonists. J. Biol. Chem. 281, 26542660
(2006).
48. Shklyaev, S. et al. Sustained peripheral expression
of transgene adiponectin offsets the development of
diet-induced obesity in rats. Proc. Natl Acad. Sci. USA
100, 1421714222 (2003).
49. Xu, A. et al. The fat-derived hormone adiponectin
alleviates alcoholic and nonalcoholic fatty liver
diseases in mice. J. Clin. Invest. 112, 91100 (2003).
50. Kamada, Y. et al. Enhanced carbon tetrachlorideinduced liver fibrosis in mice lacking adiponectin.
Gastroenterology 125, 17961807 (2003).
51. Masaki, T. et al. Adiponectin protects LPS-induced
liver injury through modulation of TNF- in KK-Ay
obese mice. Hepatology 40, 177184 (2004).
52. Sennello, J. A. et al. Regulation of T cell-mediated
hepatic inflammation by adiponectin and leptin.
Endocrinology 146, 21572164 (2005).
www.nature.com/reviews/immunol
2006 Nature Publishing Group
REVIEWS
99. Hida, K. et al. Visceral adipose tissue-derived serine
protease inhibitor: a unique insulin-sensitizing
adipocytokine in obesity. Proc. Natl Acad. Sci. USA
102, 1061010615 (2005).
100. Yang, Q. et al. Serum retinol binding protein 4
contributes to insulin resistance in obesity and type 2
diabetes. Nature 436, 356362 (2005).
101. Wang, Y. et al. Adiponectin inhibits cell proliferation
by interacting with several growth factors in an
oligomerization-dependent manner. J. Biol. Chem.
280, 1834118347 (2005).
102. Brakenhielm, E. et al. Adiponectin-induced
antiangiogenesis and antitumor activity involve
caspase-mediated endothelial cell apoptosis. Proc.
Natl Acad. Sci. USA 101, 24762481 (2004).
103. Bub, J. D., Miyazaki, T. & Iwamoto, Y. Adiponectin as a
growth inhibitor in prostate cancer cells. Biochem.
Biophys. Res. Commun. 340, 11581166 (2006).
104. Garofalo, C. & Surmacz, E. Leptin and cancer. J. Cell.
Physiol. 207, 1222 (2005).
105. Ishikawa, M. et al. Plasma adiponectin and gastric
cancer. Clin. Cancer Res. 11, 466472 (2005).
106. Miyoshi, Y. et al. Association of serum adiponectin
levels with breast cancer risk. Clin. Cancer Res.
9, 56995704 (2003).
107. Petridou, E. et al. Plasma adiponectin concentrations
in relation to endometrial cancer: a casecontrol
study in Greece. J. Clin. Endocrinol. Metab. 88,
993997 (2003).
108. Goktas, S. et al. Prostate cancer and adiponectin.
Urology 65, 11681172 (2005).
Acknowledgements
We gratefully acknowledge A. Kaser for helpful discussions
and critical reading of the manuscript. We are supported by
grants from the Austrian Science Foundation and the
Christian-Doppler Research Society (Austria).
DATABASES
The following terms in this article are linked online to:
Entrez Gene:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene
adiponectin | ADIPOR1 | ADIPOR2 | APOE | CCL2 | CRP |
CXCL8 | GLUT4 | granulocyte colony-stimulating factor |
ICAM1 | IKK | IL-1 | IL-1RA | IL-4 | IL-6 | IL-10 | IL-12 | IFN |
IRS1 | JNK1 | leptin | OBR | pentraxin-3 | plasminogenactivator inhibitor type 1 | PPAR | RBP4 | resistin | SOCS1 |
SOCS2 | SOCS3 | SREBP1C | TNF | vascular endothelial
growth factor | VASPIN | VCAM1 | visfatin | XBP1
Access to this links box is available online.