NATURE REVIEWS | ENDOCRINOLOGY VOLUME 8 | DECEMBER 2012 | 709

Paul-Langerhans Group
(H. Sell, J. Eckel),
Institute for Clinical
Diabetology (C. Habich),
German Diabetes
Center, Leibniz Center
for Diabetes Research
at the Heinrich-Heine-
University Dsseldorf,
Aufm Hennekamp 65,
40225 Dsseldorf,
Germany.
Correspondence to:
J. Eckel
eckel@
uni-duesseldorf.de
Adaptive immunity in obesity and insulin
resistance
Henrike Sell, Christiane Habich and Juergen Eckel
Abstract | Obesity is the hallmark of the metabolic syndrome and predisposes patients to the development of
major chronic metabolic diseases including type2 diabetes mellitus. Adipose tissue expansion in obesity is
characterized by increasing infiltration of proinflammatory immune cells into adipose tissue causing chronic,
low-grade inflammation. Phenotypic switching of macrophages is an important mechanism of adipose tissue
inflammation, and there is involvement of cells from the adaptive immune system in this process. T-cell
phenotype changes and recruitment of Bcells and Tcells precedes macrophage infiltration. Cytokines and
chemokines produced by immune cells influence localized and systemic inflammation, which is a pathogenic
link between obesity and insulin resistance. Antigens absorbed from the gut might contribute to T-cell
activation and recruitment into visceral adipose tissue in obesity. This Review summarizes, in the context of
obesity, the evidence for infiltration of adipose tissue by cells of the adaptive immune system, how adaptive
system cells affect innate cell populations and the influence of adaptive immune cells on the development of
insulin resistance.
Sell, H. etal. Nat. Rev. Endocrinol. 8, 709716 (2012); published online 31 July 2012; doi:10.1038/nrendo.2012.114
Introduction
Obesity is the hallmark of the metabolic syndrome,
which represents a cluster of different disorders that pre-
dispose people to the development of chronic metabolic
diseases including type2 diabetes mellitus (T2DM) and
cardiovascular disease.
1
Enlargement of adipose tissue
is the consequence of a sedentary lifestyle and increased
energy intake, and is associated with a prominent inflam-
matory response in the visceral compartment that leads
to adipose tissue dysfunction.
2
Infiltrating immune cells
perpetuate inflammation, inducing local and systemic
increases of proinflammatory cytokines and adipokines,
and provide a major link to the pathogenesis of insulin
resistance.
3
Infiltrating macrophages and adipocytes
that reside within adipose tissue are key mediators of
the inflammatory process within this tissue.
4
However,
other immune cells, such as Tcells and Bcells, have been
shown to accumulate in adipose tissue during obesity
and could have an important role in regulating the local
immune response. In this Review, we focus on the role of
the adaptive immune system in the induction of obesity-
associated adipose tissue inflammation and highlight
links to insulin resistance.
Adipose tissue inflammation in obesity
Innate immunity in adipose tissue
Traditional view
For over a decade, adipose tissue inflammation has
been recognized as a key step in the development of
obesity-associated complications. However, the precise
mechanisms and the sequence of events leading to
adipose tissue inflammation are not completely under-
stood. Two seminal publications from 2003
5,6
empha-
sized the key role of macrophage infiltration into
expanding adipose tissue, causing inflammation and
linking obesity to insulin resistance. Several mechanisms
including hypoxia, adipocyte cell death and augmented
chemokine and adipokine secretion have been proposed
to be initiators of macrophage infiltration. One study
suggested that necrotic-like adipocyte death resulting
from hypertrophy stimulates macrophage recruitment
in individuals with obesity.
7
This study was the first to
show that these infiltrating macrophages formed crown-
like structures around necrotic adipocytes.
7
There is
increased macrophage density in visceral fat of obese
animals.
8
However, it is not possible to differentiate
between apoptosis and necrosis under invivo condi-
tions as the marker to distinguish these processes can
only be detected invitro. Subsequent research showed
that apoptosis of adipocytes is a physiological process
during adipo cyte turnover that leads to accumulation of
M2-type macrophages, which are anti-inflammatory.
9

Therefore, a more complex chain of events could link
adipocyte death to adipose tissue inflammation.
Adipocyte hypertrophy might lead to local adipose
tissue hypoxia during early stages of expansion
10
and a
variety of proinflammatory adipokines are upregulated
by hypoxia.
11,12
Adipose tissue hypoxia is controversial
in humans because studies showed contradicting values
for adipose tissue oxygenation depending on the tech-
nique used.
13,14
Chemotactic factors that would augment
macrophage infiltration into the enlarged adipose tissue
Competing interests
The authors declare no competing interests.
REVIEWS
2012 Macmillan Publishers Limited. All rights reserved
710 | DECEMBER 2012 | VOLUME 8 www.nature.com/nrendo
could also be upregulated. However, the precise sequence
of events that regulates macrophage infiltration remains
to be defined.
Revised view
Adipose tissue inflammation probably results from a
complex crosstalk between adipocytes, macrophages and
other immune cells,
15
with contributions from both the
innate and the adaptive arms of the immune system. The
phenotype switching of macrophages, which involves
the change of predominantly anti-inflammatory M2
macro phage populations to include increased proportions
of proinflammatory M1 macrophages, is of particular
interest.
16,17
The presence of M1 macrophages correlates
with insulin resistance and states of over nutrition.
16
This
phenotypic switch of macrophages could be a key step of
adipose tissue inflammation and might provide a link to
the involvement of cells of the adaptive immune system.
Adipocytes themselves could have immune-cell-like
functions that lead to CD4
+
T-cell activation,
18
poten-
tially triggering inflammation independently of macro-
phage infiltration. Further work is needed to elucidate the
connection between the innate and adaptive arms of
the immune system and the adipocyte response.
Adaptive immunity in adipose tissue
The role of adaptive immune cells in obesity-induced
adipose tissue inflammation has been less well- charac ter-
ized than that of innate immune cells. How ever, a num ber
of studies have investigated the mecha nisms of adaptive
immune responses in adipose tissue inflammation.
CD4
+
Tcells
Immune cell composition can be complex in adipose
tissue depending on fat depot location (visceral or sub-
cutaneous fat) and in lean or obese states.
1921
In lean mice
about 10% of the stroma-vascular fraction (SVF) from
the visceral fat depot is composed of CD3
+
T lympho-
cytes, with a 1:3 ratio of CD8
+
to CD4
+
Tcells. The CD4
+

T-cell compartment could be further subdivided into
proinflammatory T-helper type1 (T
H
1) and T
H
17 cells,
and anti-inflammatory T
H
2 and T-regulatory cells (T
REG
)
that express forkhead box protein P3 (Foxp3). T
H
1 and
T
H
2-polarized cells are present in nearly equal amounts
and over half of the CD4
+
Tcells are T
REG
cells (numbers
Key points
Inflammation within expanding adipose tissue is a characteristic of obesity
Innate immune cells such as M1-type polarized, proinflammatory macrophages
are essential components of inflammatory processes that occur in adipose
tissue
Infiltration of adaptive immune cells precedes the accumulation of
macrophages in inflamed adipose tissue
Cytokines released from T
H
1 and T
H
17 cells could have a role in progressive
inflammation and recruitment of macrophages
Antigenic material absorbed from the gut could contribute to T-cell activation
and recruitment into visceral adipose tissue in obesity, linking nutrition to
adipose tissue inflammation
Cytokines released from cells of the adaptive immune system could contribute
to the insulin resistance that is associated with obesity
of T
H
17 cells were not measured in this study).
22
Similar
proportions of lymphocytes are found in the SVF, whereas
lymphocyte populations in visceral and subcutaneous
adipose tissues differ in composition. The lympho-
cyte populations of visceral adipose tissue are skewed
towards the innate immune system with up to 70% being
natural killer (NK) cells, Tcells and natural killer T
(NKT) cells. By contrast, lymphocytes of the subcutane-
ous adipose tissue have higher proportions of adaptive
immune system CD4
+
and CD8
+
Tcells and Bcells.
20,23
In mouse models of diet-induced obesity, T-cell popu-
lations differ in adipose tissue. A higher CD8
+
:CD4
+

T-cell ratio is found in visceral adipose tissue of high-
fat-diet fed mice compared with lean mice. Diet-induced
obesity also leads to a dramatic increase in T
H
1-polarized
cells, whereas the T
H
2-polarized fraction is significantly
reduced by ~50%. The T
H
17 subset in visceral adipose
tissue constitutes <1% of the CD4
+
population after
feeding with a high-fat diet. Furthermore, the T
H
1:T
REG

cell ratio in visceral adipose tissue during diet-induced
obesity changes from 1.5:1 to 6.5:1,
24
with a significant
reduction in T
REG
cells of about 70%.
22,24
These data indi-
cate that the numbers of T
H
1 cells are a dynamic vari-
able that is affected by diet-induced obesity.
24
Unlike
visceral adipose tissue, the proportions of CD4
+
and
CD8
+
T-cell subsets in subcutaneous adipose tissue
were reduced, whereas T
REG
numbers did not change
during obesity.
20,22,23
Interestingly, numbers of IL-17-
secreting Tcells increased substantially after feeding
with a high-fat diet. IL-17 contributes to the regulation
of adipogenes is and glucose metabolism in mice.
25
Observations made during studies of humans who are
lean or obese show similar patterns. In adipose-tissue
samples from patients with obesity, FOXP3 transcripts
were detectable in subcutaneous and visceral adipose
tissue, with higher FOXP3 levels in subcutaneous
adipose tissue.
22
Another report described a change in
the T
H
1:T
REG
ratio from 6:1 in people who are lean to 12:1
in humans with obesity.
24
Moreover, people with obesity
have increased numbers of Tcells (both CD4
+
and CD8
+
)
and NK cells, and raised expression of IFNG and CCL5
mRNA in visceral, but not subcutaneous, adipose
tissue.
19,2628
A positive association between CD3
+
T-cell
numbers and IFNG mRNA expression in adipose tissue
with BMI and waist circumference was shown in a cohort
of individuals with T2DM and indicates that T
H
1 cells
are involved in obesity-related metabolic diseases.
26,29,30

Therefore, visceral and subcutaneous fat depots differ
in adaptive immune cell composition (Box1). During
obesity, a shift from anti-inflammatory Tcells to pro-
inflammatory Tcells occurs in rodents and humans,
particularly in the visceral depot, which contributes to
diabetes-associated adipose tissue inflammation.
Immune regulation in adipose tissue
In the adipose tissue of individuals without obesity, adap-
tive immune cells are present and maintain immune
and metabolic balance. Macrophage activation is crucial
in adipose tissue inflammation and is influenced by
adap tive immune cells. IFN-secreting T
H
1 cells and
REVIEWS
2012 Macmillan Publishers Limited. All rights reserved
NATURE REVIEWS | ENDOCRINOLOGY VOLUME 8 | DECEMBER 2012 | 711
IL-17-secreting T
H
17 cells stimulate proinflammatory
macrophage functions by inducing the release of IL-6
and TNF. By contrast, anti-inflammatory T
H
2 cells,
which secrete IL-4 and IL-13, and T
REG
cells regulate
macro phage function by promoting differentiation
towards an M2 macrophage type (Box2).
1,31,32
Reconstitution studies show that lymphocyte-free
recombinant-activating gene (RAG) null mice, which
lack the ability to synthesize functional T-cell or B-cell
receptors, develop a diabetic phenotype when fed a high-
fat diet.
24
These results provide strong evidence that
CD4
+
Tcells, particularly the T
H
2 subset, regulate obesity
and glucose homeostasis.
24
Adoptive transfer of CD4
+

Tcells reduced weight gain and serum levels of obesity-
associated chemokines and adipokines, such as leptin and
resistin. Moreover, glucose tolerance was normalized with
lowered fasting insulin and glucose levels, and improved
insulin sensitivity.
24
The under lying mechanisms by
which CD4
+
Tcells affect insulin sensitivity are not clear.
The authors of the reconstitution studies suggest that the
induction of IL-10-secreting M2 macrophages by IL-10,
TGF- secreting T
REG
cells and T
H
2 cells is one potential
mechanism. M2 macro phages might promote insulin sen-
sitivity through IL-10-mediated reversal of insulin resist-
ance induced by TNF.
24
In lean mice, M2 macrophages
are present in adipose tissue. During the development of
obesity, there is a shift to M1-type macrophages,
33,34
which
might be caused by steadily increasing proportions of T
H
1
cells in relation to T
REG
and T
H
2 cells.
24
This pool of T
REG

and T
H
2 cells, which is usually constant, gradually fails to
regulate an expanding population of T
H
1 cells, leading to
a progressively proinflammatory environment that pro-
motes insulin resistance. Factors that drive T
H
1 cell influx
and/or expansion in visceral adipose tissue are unclear,
but might include antigen-driven expansion,
27
production
of the T
H
1-derived chemoattractant CCL5 (also known as
RANTES)
27
and chemokines CCL20
26
by adipocytes and
CXCL12 (also known as SDF-1) produced by preadipo-
cytes.
30
Interestingly, the clonal diversity of Tcells in vis-
ceral adipose tissue is very restricted, indicating an active
adaptive immune response occurring in adipose tissue
of individuals with obesity and expansion of potentially
autoimmune Tcells.
35
It is also possible that T
REG
function is suboptimal in
the inflammatory visceral adipose tissue environment,
as suggested by experiments with an experimental auto-
immune encephalomyelitis disease model, in which T
REG

cells expanded but failed to prevent disease and suppress
inflam mation.
36
Another study indicated that the loss of
T
REG
from the visceral fat might be the primary effect
of adipose tissue inflammation.
22
Leptin can suppress
T
REG
proliferation.
37
Reduction of T
REG
numbers in adipose tissue is associ-
ated with profound alterations in adipose-tissue macro-
phage and effector T-cell populations; in addition to
loss of T
REG
cells, there is potentially an accompanying
reduction in the magnitude of other anti- inflammatory
T-cell subsets. The reduction in T
REG
numbers in
obesity might result from reduced local differentiation
rather than impaired homing and could be a functional
consequence of macrophage-derived inflammatory
signals.
38
Although these studies show the important
role that the balance of different CD4
+
T-cell subsets
has in adipose tissue inflammation, potential effects of
other adaptive immune cell populations such as cytotoxic
CD8
+
Tcells, NK cells, NKTcells or B lymphocytes on
these processes cannot be ruled out.
CD8
+
Tcells, NK, NKT and Bcells
In a mouse model of obesity induced by a high-fat diet,
CD8
+
effector Tcells and then macrophages infiltrated
visceral adipose tissue. CD8
+
cells are involved in macro-
phage differentiation, activation and migration, thereby
initiating inflammatory cascades in adipose tissue that
lead to insulin resistance.
39
NK cells are present in large numbers in visceral
adipose tissue where they might be involved in the
regulation of adipose tissue homeostasis.
23
During diet-
induced obesity in mice, NK numbers decreased in a
leptin-dependent manner.
23
NKTcells could have a
role in adipose tissue inflammation and glucose intoler-
ance in diet-induced mice with obesity.
40
NKTcells are
described as innate-like T lymphocytes, because they
possess invariant pattern recognition receptors instead of
antigen- specific T-cell receptors,
41
and release a mixture
of T
H
1 and T
H
2 cytokines, such as IFN- and IL-4, thereby
shaping subsequent adaptive immune responses.
42

NKTcells are present at high levels in the SVF of white
adipose tissue.
20,23
During obesity in mice induced by a
high-fat diet, NKTcells infiltrate the visceral adipose
tissue along with macrophages during the develop ment
Box 1 | Depot-specific differences in adipose tissue inflammation
Obesity is characterized by heterogeneous aetiology with excess adipose tissue
being stored predominantly either in subcutaneous or in visceral adipose tissue
depots. Epidemiological data strongly suggest that increased amounts of visceral
adipose tissue in obesity are associated with a higher risk of obesity-related
diseases compared to subcutaneous obesity,
2,86
and there are differences
between patterns of adipokine secretion and inflammation in these two depots.
23

Macrophage infiltration is greater in visceral adipose tissue than the subcutaneous
depot in people with obesity.
87
T
REG
depletion in visceral adipose tissue is associated
with inflammation in obesity in rodents and in humans,
38
and there is increased
infiltration of Tcells and NKcells.
28
IFN- expression is increased in NKcells from
visceral adipose tissue compared with NKcells from the subcutaneous depot.
Abbreviations: NK, natural killer; T
REG
, T-regulatory cell.
Box 2 | T-cell-derived cytokines modulate macrophage polarization
Macrophage activation is a crucial step in the development of adipose tissue
inflammation and is mediated by adaptive immune cells. T
H
2 cells and T
REG

promote an anti-inflammatory M2 macrophage polarization through production
of IL-4, IL-10 or IL-13, whereas T
H
1 and T
H
17 cells release IFN- and IL-17, which
stimulate proinflammatory M1 macrophage differentiation.
1,31,32
Eosinophils can
also influence macrophage polarization by producing IL-4.
88
During the course
of obesity development, increasing ratios of T
H
1:T
REG
and T
H
1:T
H
2 cells could be
responsible for a shift of macrophages to the proinflammatory M1 macrophage
phenotype.
24
Increasing numbers of T
H
1 cells could progressively create a
proinflammatory environment, which promotes insulin resistance. This view of
T-cell-specific cytokine influence on macrophage polarization corresponds to
the chronological sequence of how adaptive immune system cell population
characteristics change in mouse models of obesity.
1,30,43
Abbreviations: T
H
, T-helper cell; T
REG
, T-regulatory cell.
REVIEWS
2012 Macmillan Publishers Limited. All rights reserved
712 | DECEMBER 2012 | VOLUME 8 www.nature.com/nrendo
of glucose intolerance. When fed a high-fat diet,
2-microglobulin-knockout mice, which lack NKTcells,
had improved glucose intolerance and decreased visceral
adipose tissue inflammation compared with similarly fed
wild type mice with comparable obesity. Subsequent acti-
vation of NKTcells by -galactosylceramide increased
glucose intolerance and adipose tissue inflammation
with raised macrophage numbers.
40
Therefore, NKTcells
might have a crucial role in the development of glucose
intolerance and adipose inflammation in obesity. The
underlying mechanisms of NKT-cell activation in obesity
are yet to be identified.
The role of B lymphocytes in the development of
insulin resistance is less clear, despite the evidence that
these cells are recruited to adipose tissue, before Tcells,
shortly after the initiation of a high-fat diet
43
and that
B-cell activation is increased in individuals with T2DM.
44

Bcells accumulated in visceral adipose tissue in high-
fat-diet fed mice with obesity,
35
and knockout mice that
lack Bcells had improved glucose tolerance and insulin
sensitivity regardless of weight gain, compared with
wild type mice, during a high-fat diet. Reconstitution
with wild type Bcells from high-fat-diet fed mice led
to impaired glucose metabolism and decreased insulin
sensitivity as a result of the antigen-dependent activation
of Tcells (T
H
1 and CD8
+
Tcells), proinflammatory M1
macrophages and secretion of pathogenic IgG antibodies
from Bcells. Treatment with a Bcell-depleting antibody
attenuated these effects, whereas transfer of IgG from
mice with diet-induced obesity quickly induced insu lin
resis tance and glucose intolerance. Moreover, insu lin
resis tance in humans with obesity was associated with
IgG auto antibodies directed against a specific profile of
self antigens, which were mostly intracellular proteins
found in tissues containing immune cells.
35
Based on these studies in mouse models, lymphocyte
infiltration in adipose tissue might occur in a chronological
sequence that begins with B and T lymphocytes (T
H
1 and
CD8
+
Tcells) being recruited during early obesity-induced
inflammation by preadipocyte or adipocyte-derived
chemokines like CCL5 and CXCL5 (Figure1).
24,27,30,35,39,43

These cells direct the local inflammatory process through
the release of proinflammatory T
H
1 cytokines such as
IFN-, which promote M1 macrophage recruitment
by inducing preadipocytes and adipocytes to release
chemokines and activating macro phages.
1,29,45
In humans,
the mechanisms are less clear and additional studies are
required to elucidate these processes.
Adaptive immunity in the gut
T-cell infiltration is an important early step of visceral
adipose tissue inflammation in diet-induced obesity.
As yet, it is unclear why these cells are attracted to this
tissue. Researchers have mainly focused on endo genous or
dietary factors such as saturated fatty acids.
46,47
However,
there is increasing evidence that the intestinal microflora
is important in obesity and metabolic syndrome,
4850

demon strated by studies of germ-free mice in which
dietary energy harvest was manipulated by altering the
microbiome.
48,51,52
Lipids could exert stress on the intesti-
nal epithelium by causing temporary damage to epithelial
lining of the villous tips,
53
promoting intestinal absorp-
tion of antigenic material from the gut, which then could
induce inflammatory immune responses, especially in
tissues with close proximity to the gut. This effect could
be exacerbated by the lipid abundance in a high-fat diet.
a c b
M
2
macrophage
T
H
2
T
REG
M
1
macrophage
T
H
1
CD8
+
T cells
Adipocytes
NK cell
B cell
Lean Early obesity Established obesity
IL-10
CCL5
CXCL12
CCL20
IFN-
CCL2
IL-17
Figure 1 | Development of adipose tissue inflammation in obesity. a | In lean rodents, M2-polarized macrophages, T
REG
and
T
H
2-polarized Tcells predominate in adipose tissue. Adipose tissue inflammation is suppressed by IL-10 secreted by
Tcells. b | Early in obesity, there is a shift in T-cell populations towards CD8
+
Tcells and T
H
1-polarized lymphocytes, and
Bcells are recruited to adipose tissue. Increased release of chemotactic adipokines and chemokines such as CCL5,
CXCL12 and CCL20 by enlarged adipocytes contributes to this recruitment of proinflammatory cells of the adaptive
immune system to adipose tissue. c | As obesity progresses, an infiltration of NKcells and proinflammatory M1-polarized
macrophages might be triggered by increased production of INF- and chemokines such as CCL2 released from CD8
+
and
T
H
1-polarized lymphocytes. Other factors released by these Tcells such as IL-17 could contribute to insulin resistance of
adipocytes. Abbreviations: NK, natural killer; T
H
, T-helper cell; T
REG
, T-regulatory cell.
REVIEWS
2012 Macmillan Publishers Limited. All rights reserved
NATURE REVIEWS | ENDOCRINOLOGY VOLUME 8 | DECEMBER 2012 | 713
Intestinal absorption of dietary fat promotes the uptake
of gut-bacteria-derived lipopolysaccharide and protein
antigens. In a mouse model, ovalbumin and lipopoly-
saccharide were both associated with the presence of
chylo microns, which are involved with dietary lipid
transport.
54,55
Chylomicrons are partly cleared in adipose
tissue,
56,57
which raises the question as to whether fat
absorption also promotes protein absorption into adipose
tissue and if this stimulates T-cell responses and inflamma-
tion. A subsequent study demonstrated that fat absorption
does indeed promote antigen uptake into adipose tissue
(Figure2).
58
The apparent chylomicron-promoted absorp-
tion of an antigen such as ovalbumin and its uptake into
tissues does not necessarily cause inflammatory immune
responses. Naive mice typically develop oral tolerance
to absorbed antigens, which protects against allergic or
inflammatory responses.
59
Naive mice fed with o valbumin-
enriched diets had no T-cell infiltration into adipose tissue,
even though antigen was present. By contrast, lack of
immuno logical tolerance to this antigen caused marked
inflammatory responses in mesenteric (but not subcuta-
neous) adipose tissue, which were increased by a high-fat
diet.
58
Over time, these responses resulted in a decreasing
glucose tolerance. The possible reason for the late occur-
rence of glucose intolerance was the presence of T
REG
,
which initially suppressed inflammation.
58
The results of
this study indicate a potential role of gut-absorbed antigens
in T-cell activation and recruitment in visceral adipose
tissue during diet-induced obesity. A proinflammatory
milieu within the visceral fat, perhaps through increased
free fatty acids, might impair tolerance to these antigens
and lead to chronic inflammation. Further studies are
needed to establish whether other proteins and bacterial
structures have similar effects, particularly in people with
obesity and an altered gut microbiota.
Almost immediately after bariatric surgery, patients
have improved insulin sensitivity and reduced inflamma-
tion, which occurs before marked weight loss.
6062
Changes
in the gut microbiota after bariatric surgery suggest that
altered microbial structures influence the recruitment and
activation of immune cells, contributing to suppression
of inflammatory processes and improve metabolic status.
Experimental models and studies in humans have sup-
ported this concept through investigating the influence
of prebiotics and probiotics on the gut microbiota and
metabolic function.
63
Although this subject is complex
and no bacterial species has been strongly associated with
the obese phenotype, modulating gut microbiota might
control the development of metabolic diseases associated
with obesity.
52,64
Insulin resistance
Adaptive mediators of insulin resistance
Links between obesity, insulin resistance and the adap-
tive immune system effects on adipose tissue inflamma-
tion indicate that mediators released from these immune
cells could be involved in chronic insulin resistance. T-cell
recruitment precedes macrophage infiltration and occurs
in parallel with the induction of insulin resistance.
30,39

Another study demonstrated that T-cell recruitment and
T
H
1 polarization happens after induction of insulin resist-
ance and after adipose tissue expansion and macrophage
infiltration in diet-induced obesity,
19
although the authors
of the study suggest that early T-cell priming for IFN-
production during the development of obesity contributes
to the progression of adipose tissue inflammation and
insulin resistance. Another report controversially suggests
that inflammation mediated by Tcells in adipose tissue is
not causally related to insulin resistance.
65
In that study,
mice with increased inflammation, resulting from disrup-
tion of TGF- signalling by Tcells, do not have increased
insulin resistance. However, the difference between study
results could be attributable to the different animal models
of obesity and insulin resistance used, making it difficult
to determine the exact time of the onset of adipose tissue
inflammation and insulin resistance. This difference
Adipose
tissue
a b
Gut
microbiota
Lean phenotype Obesity
Gut
microbiota
Clearance
T-cell
infltration
Infammation
Chylomicron
LPS
TG
OVA
T cell
Figure 2 | Gut-derived antigens promote T-cell activation in adipose tissue. a | Lean individuals do not have high levels of
inflammation in adipose tissue and the microbiota (brown) properties reflect their diet. b | A high-fat diet contains high levels of
triglycerides, which promote the intestinal absorption of protein antigens such as ovalbumin. During the development of obesity,
gut microflora is altered (blue) and microbial structures like lipopolysaccharide are absorbed by the gut. Food-derived antigens
and lipolysaccharide are associated with chylomicrons, which transport triglycerides and are cleared in adipose tissue. Antigens
associated with the chylomicrons could be absorbed leading to the recruitment and activation of Tcells into adipose tissue,
contributing to inflammatory processes. Abbreviations: LPS, lipopolysaccharides; OVA, ovalbumin; TG, triglycerides.
REVIEWS
2012 Macmillan Publishers Limited. All rights reserved
714 | DECEMBER 2012 | VOLUME 8 www.nature.com/nrendo
between studies also substantially limits extrapo lation of
the observed effects to humans. Early insulin resistance
(within 3days) induced by a high-fat diet might be related
to acute lipid overload and lipotoxicity in skeletal muscle
and liver, independent of adipose tissue inflammation,
whereas the later stage of insulin resistance in obesity is
largely mediated by macrophage-induced inflamma-
tion.
66
In one study, measurements of circulating markers
of immune cell activity such as neopterin, which is pro-
duced by macrophages and indicates cellular activation
and soluble CD25, expressed by activated lymphocytes,
were used to develop scores of innate and adaptive activa-
tion, and showed an association between insulin resistance
and increased activation of the adaptive and innate arms
of the immune system in humans.
67
A potential anti-inflammatory role of insulin in adi-
pose tissue inflammation has been proposed, whereby
insulin promotes polarization of effector Tcells towards
a T
H
2 phenotype.
68
Improvement of insulin resistance in
humans, due to weight loss after gastric banding, is associ-
ated with a decreased T
H
1:T
H
2 ratio, which was more pro-
nounced in people with impaired glucose tolerance than
in patients with T2DM despite similar decreases in body
weight, glucose and insulin levels.
69
Improved glycaemic
control or improved insulin signalling might contribute
to increased T
H
2 differentiation.
T-cell profiles in patients with insulin resistance are
altered, which could indicate that T-cell factors are linked
to disturbed insulin sensitivity. In patients with T2DM, cir-
culating Tcells produce increased levels of IL-17 and IFN-
and promote inflammation.
70
In patients with the meta-
bolic syndrome, circulating levels of both T
H
1-secreted
cyto kines (IL-2, IL-12 and INF-) and T
H
2-produced
cyto kines (IL-4, IL-5 and IL-13), were observed and were
nega tively associated with adipo nectin, but positively-
associated with high homeostasis model assessment of
insulin resistance scores and high-sensitivity C-reactive
protein (hs-CRP) test results, which are established
indicators of the metabolic syndrome.
71
Whether raised
CRP also originates from Tcells within adipose tissue is
unclear, but circulating CRP levels might mirror the milieu
in the adipose tissue of patients with metabolic syndrome.
Several cytokines produced by T
H
1 or T
H
17 cells have
been linked to insulin resistance invitro and invivo.
IL-17 suppresses adipogenesis and ablation of IL-17 pro-
tects from insulin resistance induced by a high-fat diet.
25

The chemokines described above, such as CCL20 and
CXCL12, which attract lymphocytes to adipose tissue
could also have a role in insulin resistance. The role of
CXCL12 in the development of insulin resistance and
T2DM might not be directly related to adipose tissue,
as CXCL12 promotes -cell survival in streptozotocin-
treated rodents.
72
However, inflammation in adipose
tissue might be controlled by production of IL-13 and
IL-4by adipocytes.
73
IL-17, CXCL5, CCL2 and other chemotactic proteins
can induce insulin resistance by activation of various
path ways that interact with the insulin signalling cas-
cade. Different proinflammatory factors target stress-
activated kinases such as mitogen-activated pro tein
kinase 8 (MAPK8) and inhibitor of nuclear factor -B
kinase subunit (IKK-).
74
Activation of MAPK8 and
IKK- in turn lead to inhibitory serine phosphorylation
of insulin receptor substrate1 (IRS1) and IRS2 and sub-
sequent insulin resistance.
75,76
Other possible mechanisms
linking inflammation in adipose tissue to insulin resist-
ance include mitochondrial dysfunction and ER stress,
which have been reviewed elsewhere.
77
Adaptive immunotherapy for insulin resistance
Lymphocyte markers, chemoattractants and inflammatory
pathways are potential therapeutic targets in the adaptive
immune system. Surface markers of lymphocytes such as
CD19, CD22 and CD79a and CD79b could be targeted
by antibodies, such as rituximab,
35
which is a monoclonal
antibody specific for human CD20 expressed by Bcells
and is used to treat cancer. Rituximab has also been used
for therapy of autoimmune diabetes, and -cell destruc-
tion seems to be delayed by large reductions in B-cell
numbers.
78
As rituximab is already used to treat inflam-
matory diseases such as rheumatoid arthritis, it could also
be effective against adipose tissue inflammation.
79
PPAR- activation, which has been used as a therapy for
T2DM, decreases adipose tissue inflammation by reducing
T-cell-dependent inflammation.
33
Infiltration of lympho-
cytes and macrophages was decreased by PPAR- agonists
in diet-induced obesity and insulin sensitivity improved
after treatment. PPAR- regulates macro phage polariza-
tion and, therefore, might be a target to modulate adipose
tissue inflammation and insulin sensitivity.
73
PPAR- ago-
nists inhibited T
H
1 and T
H
17 responses in experimental
allergic encephalo myelitis and could moderate adaptive
immune cell responses in adipose tissue.
80
Inducing the release of the cytokines that suppress
inflammation in adipose tissue, or stimulating their
receptors might also have therapeutic potential. IL-33 is
a newly identified member of the IL-1 cytokine family
that induces the production of T
H
2 cytokines and attenu-
ates adipose tissue inflammation in genetically obese
mice.
81
IL-10 modulates T
H
1 cytokine production and
individuals with obesity have lower circulating levels of
this anti- inflammatory cytokine than people without
obesity. Although depletion of IL-10 does not aggravate
obesity-induced inflammation and insulin resistance,
82
it
does protect from diet-induced insulin resistance in skele-
tal muscle.
83
The potential role of IL-10 in adipose tissue
inflammation should be investigated.
Exercise and dietary supplements such as -lipoic
acid could also reduce adipose tissue inflammation and
has been shown to significantly decrease macrophage
numbers in the crown-like structures within adipose
tissue and reduce insulin resistance in mice with diet-
induced obesity.
84
Exercise reduces macrophage infil-
tration into adipose tissue of humans with obesity and
decreases proinflammatory adipokines.
85
However, it has
not yet been determined if exercise or dietary intervention
also affects the number and polarization of Tcells.
Although these potential therapeutic options have been
studied in murine models or discussed theoretically, most
have not been tested in humans. Future work is needed
REVIEWS
2012 Macmillan Publishers Limited. All rights reserved
NATURE REVIEWS | ENDOCRINOLOGY VOLUME 8 | DECEMBER 2012 | 715
to provide endocrinologists with potent therapeutic
strategies to reduce adipose tissue inflammation and its
obesity-associated metabolic complications.
Conclusion
Knowledge of the action of the innate and adaptive
arms of the immune system in adipose tissue of indivi-
duals with obesity and metabolic disorders such as
insulin resistance and T2DM has increased considerably.
Infiltration of primarily proinflammatory cell types of the
adaptive immune system into adipose tissue at the onset
of obesity in rodents has been demonstrated, illustrat-
ing a complex interplay between different cell types in
this tissue. The innate immune system has been shown
to be a major factor in established obesity. M1-polarized
macrophages have an important role in adipose tissue
inflammation and the development of insulin resist-
ance in rodents and humans. The role of adaptive
immune cells in the development of insulin resistance
is still unclear as the composition of adaptive cell pools
within adipose tissue is modulated in early obesity and
it is not clear if insulin resistance is induced in parallel.
However, T-cell-derived cytokines modulate macro-
phage phenotype switching, which is directly linked
to insulin resistance. There is as yet insufficient data to
demonstrate the concept of adaptive cells contributing
to adipose tissue inflammation in humans and further
studies are needed. The link between the gut and adipose
tissue inflammation particularly warrants further inves-
tigation. New insight into this connection would help to
understand how weight loss ameliorates metabolic traits
and inflammation in patients with obesity. Targeting dif-
ferent immune cells at different stages of obesity could
eventually lead to novel therapeutic approaches for the
metabolic syndrome. Established drugs for the therapy
of insulin resistance such as PPAR- agonists could also
be used to target adipose tissue inflammation in patients
with obesity. Stimulating anti-inflammatory cytokines
with small molecules or using antibodies against surface
markers of immune-cell subtypes, could be new strategies
to combat obesity-related metabolic disorders.
Review criteria
The studies in this Review were selected from the authors
database or identified by a literature search in PubMed
for articles published in English from 2000 to 2011. The
search terms used were adaptive immune system obesity,
adaptive immune system insulin resistance, Tcell
obesity, Tcell insulin resistance. Additional relevant
references cited in these articles were also included.
1. Ouchi, N., Parker, J.L., Lugus, J.J. & Walsh, K.
Adipokines in inflammation and metabolic
disease. Nat. Rev. Immunol. 11, 8597 (2011).
2. Desprs, J.P. & Lemieux, I. Abdominal obesity
and metabolic syndrome. Nature 444, 881887
(2006).
3. Olefsky, J.M. & Glass, C.K. Macrophages,
inflammation, and insulin resistance. Annu. Rev.
Physiol. 72, 219246 (2010).
4. Hotamisligil, G.S. Inflammation and metabolic
disorders. Nature 444, 860867 (2006).
5. Weisberg, S.P. etal. Obesity is associated with
macrophage accumulation in adipose tissue.
J.Clin. Invest. 112, 17961808 (2003).
6. Xu, H. etal. Chronic inflammation in fat plays a
crucial role in the development of obesity-related
insulin resistance. J. Clin. Invest. 112,
18211830 (2003).
7. Cinti, S. etal. Adipocyte death defines
macrophage localization and function in adipose
tissue of obese mice and humans. J. Lipid Res.
46, 23472355 (2005).
8. Murano, I. etal. Dead adipocytes, detected as
crown-like structures, are prevalent in visceral
fat depots of genetically obese mice. J. Lipid
Res. 49, 15621568 (2008).
9. Fischer-Posovszky, P., Wang, Q.A.,
Asterholm,I.W., Rutkowski, J.M. & Scherer, P.E.
Targeted deletion of adipocytes by apoptosis
leads to adipose tissue recruitment of
alternatively activated M2 macrophages.
Endocrinology 152, 30743081 (2011).
10. Trayhurn, P. & Wood, I.S. Adipokines:
inflammation and the pleiotropic role of white
adipose tissue. Br. J. Nutr. 92, 347355 (2004).
11. Chen, B. etal. Hypoxia dysregulates the
production of adiponectin and plasminogen
activator inhibitor-1 independent of reactive
oxygen species in adipocytes. Biochem. Biophys.
Res. Commun. 341, 549556 (2006).
12. Hosogai, N. etal. Adipose tissue hypoxia in
obesity and its impact on adipocytokine
dysregulation. Diabetes 56, 901911 (2007).
13. Pasarica, M. etal. Reduced adipose tissue
oxygenation in human obesity: evidence for
rarefaction, macrophage chemotaxis, and
inflammation without an angiogenic response.
Diabetes 58, 718725 (2009).
14. Goossens, G.H. etal. Increased adipose
tissue oxygen tension in obese compared
with lean men is accompanied by insulin
resistance, impaired adipose tissue
capillarization, and inflammation. Circulation
124, 6776 (2011).
15. Sun, K., Kusminski, C.M. & Scherer, P.E.
Adipose tissue remodeling and obesity. J. Clin.
Invest. 121, 20942101 (2011).
16. Lumeng, C.N., Bodzin, J.L. & Saltiel, A.R.
Obesity induces a phenotypic switch in adipose
tissue macrophage polarization. J. Clin. Invest.
117, 175184 (2007).
17. Fleming, B.D. & Mosser, D.M. Regulatory
macrophages: setting the threshold for
therapy. Eur. J. Immunol. 41, 24982502
(2011).
18. Meijer, K. etal. Human primary adipocytes
exhibit immune cell function: adipocytes prime
inflammation independent of macrophages.
PLoS ONE 6, e17154 (2011).
19. Strissel, K.J. etal. T-cell recruitment and Th1
polarization in adipose tissue during diet-
induced obesity in C57BL/6 mice. Obesity
(Silver Spring) 18, 19181925 (2010).
20. Caspar-Bauguil, S. etal. Adipose tissue
lymphocytes: types and roles. J. Physiol.
Biochem. 65, 423436 (2009).
21. Kaminski, D.A. & Randall, T.D. Adaptive
immunity and adipose tissue biology. Trends
Immunol. 31, 384390 (2010).
22. Feuerer, M. etal. Lean, but not obese, fat is
enriched for a unique population of regulatory
Tcells that affect metabolic parameters. Nat.
Med. 15, 930939 (2009).
23. Caspar-Bauguil, S. etal. Adipose tissues as an
ancestral immune organ: site-specific change in
obesity. FEBS Lett. 579, 34873492 (2005).
24. Winer, S. etal. Normalization of obesity-
associated insulin resistance through
immunotherapy. Nat. Med. 15, 921929 (2009).
25. Ziga, L.A. etal. IL-17 regulates adipogenesis,
glucose homeostasis, and obesity. J. Immunol.
185, 69476959 (2010).
26. Duffaut, C. etal. Interplay between human
adipocytes and T lymphocytes in obesity: CCL20
as an adipochemokine and T lymphocytes as
lipogenic modulators. Arterioscler. Thromb. Vasc.
Biol. 29, 16081614 (2009).
27. Wu, H. etal. T-cell accumulation and regulated
on activation, normal Tcell expressed and
secreted upregulation in adipose tissue in
obesity. Circulation 115, 10291038 (2007).
28. ORourke, R.W. etal. Depot-specific differences
in inflammatory mediators and a role for NK cells
and IFN- in inflammation in human adipose
tissue. Int. J. Obes. (Lond.) 33, 978990 (2009).
29. Rocha, V.Z. & Folco, E.J. Inflammatory concepts
of obesity. Int. J. Inflam. 2011, 529061 (2011).
30. Kintscher, U. etal. T-lymphocyte infiltration in
visceral adipose tissue: a primary event in
adipose tissue inflammation and the
development of obesity-mediated insulin
resistance. Arterioscler. Thromb. Vasc. Biol. 28,
13041310 (2008).
31. Odegaard, J.I. etal. Macrophage-specific PPAR
controls alternative activation and improves
insulin resistance. Nature 447, 11161120
(2007).
32. Tiemessen, M.M. etal. CD4+CD25+Foxp3+
regulatory Tcells induce alternative activation of
human monocytes/macrophages. Proc. Natl
Acad. Sci. USA 104, 1944619451 (2007).
33. Foryst-Ludwig, A. etal. PPAR activation
attenuates T-lymphocyte-dependent inflammation
of adipose tissue and development of insulin
resistance in obese mice. Cardiovasc. Diabetol.
9, 64 (2010).
34. Stienstra, R. etal. Peroxisome proliferator-
activated receptor activation promotes
infiltration of alternatively activated
REVIEWS
2012 Macmillan Publishers Limited. All rights reserved
716 | DECEMBER 2012 | VOLUME 8 www.nature.com/nrendo
macrophages into adipose tissue. J. Biol. Chem.
283, 2262022627 (2008).
35. Winer, D.A. etal. Bcells promote insulin
resistance through modulation of Tcells and
production of pathogenic IgG antibodies. Nat.
Med. 17, 610617 (2011).
36. Korn, T. etal. Myelin-specific regulatory Tcells
accumulate in the CNS but fail to control
autoimmune inflammation. Nat. Med. 13,
423431 (2007).
37. De Rosa, V. etal. A key role of leptin in the
control of regulatory Tcell proliferation. Immunity
26, 241255 (2007).
38. Deiuliis, J. etal. Visceral adipose inflammation
in obesity is associated with critical alterations
in tregulatory cell numbers. PLoS ONE 6,
e16376 (2011).
39. Nishimura, S. etal. CD8+ effector Tcells
contribute to macrophage recruitment and
adipose tissue inflammation in obesity. Nat.
Med. 15, 914920 (2009).
40. Ohmura, K. etal. Natural killer Tcells are
involved in adipose tissues inflammation and
glucose intolerance in diet-induced obese mice.
Arterioscler. Thromb. Vasc. Biol. 30, 193199
(2010).
41. Van Kaer, L., Parekh, V.V. & Wu, L. Invariant
natural killer Tcells: bridging innate and adaptive
immunity. Cell Tissue Res. 343, 4355 (2011).
42. Van Kaer, L. NKTcells: T lymphocytes with innate
effector functions. Curr. Opin. Immunol. 19,
354364 (2007).
43. Duffaut, C., Galitzky, J., Lafontan, M. &
Bouloumie, A. Unexpected trafficking of immune
cells within the adipose tissue during the onset
of obesity. Biochem. Biophys. Res. Commun. 384,
482485 (2009).
44. Jagannathan, M. etal. Toll-like receptors regulate
Bcell cytokine production in patients with
diabetes. Diabetologia 53, 14611471 (2010).
45. Rocha, V.Z. etal. Interferon-, a Th1 cytokine,
regulates fat inflammation: a role for adaptive
immunity in obesity. Circ. Res. 103, 467476
(2008).
46. Suganami, T. etal. Role of the Toll-like receptor 4/
NF-kappaB pathway in saturated fatty acid-
induced inflammatory changes in the interaction
between adipocytes and macrophages.
Arterioscler. Thromb. Vasc. Biol. 27, 8491 (2007).
47. Shi, H. etal. TLR4 links innate immunity and
fatty acid-induced insulin resistance. J. Clin.
Invest. 116, 30153025 (2006).
48. Turnbaugh, P.J. etal. An obesity-associated gut
microbiome with increased capacity for energy
harvest. Nature 444, 10271031 (2006).
49. Vijay-Kumar, M. etal. Metabolic syndrome and
altered gut microbiota in mice lacking Toll-like
receptor 5. Science 328, 228231 (2010).
50. Ding, S. etal. High-fat diet: bacteria interactions
promote intestinal inflammation which precedes
and correlates with obesity and insulin
resistance in mouse. PLoS ONE 5, e12191
(2010).
51. Tilg, H. & Kaser, A. Gut microbiome, obesity, and
metabolic dysfunction. J. Clin. Invest. 121,
21262132 (2011).
52. Delzenne, N.M., Neyrinck, A.M. & Cani, P.D.
Modulation of the gut microbiota by nutrients
with prebiotic properties: consequences for host
health in the context of obesity and metabolic
syndrome. Microb. Cell Fact. 10 (Suppl. 1), S10
(2011).
53. Kvietys, P.R., Specian, R.D., Grisham, M.B. &
Tso, P. Jejunal mucosal injury and restitution:
role of hydrolytic products of food digestion. Am.
J. Physiol. 261, G384G391 (1991).
54. Wang, Y. etal. Chylomicrons promote intestinal
absorption and systemic dissemination of
dietary antigen (ovalbumin) in mice. PLoS ONE 4,
e8442 (2009).
55. Ghoshal, S., Witta, J., Zhong, J., de Villiers, W. &
Eckhardt, E. Chylomicrons promote intestinal
absorption of lipopolysaccharides. J. Lipid Res.
50, 9097 (2009).
56. Bickerton, A.S. etal. Preferential uptake of
dietary Fatty acids in adipose tissue and muscle
in the postprandial period. Diabetes 56,
168176 (2007).
57. Karpe, F., Humphreys, S.M., Samra, J.S.,
Summers, L.K. & Frayn, K.N. Clearance of
lipoprotein remnant particles in adipose tissue
and muscle in humans. J. Lipid Res. 38,
23352343 (1997).
58. Wang, Y. etal. T-lymphocyte responses to
intestinally absorbed antigens can contribute to
adipose tissue inflammation and glucose
intolerance during high fat feeding. PLoS ONE 5,
e13951 (2010).
59. Chehade, M. & Mayer, L. Oral tolerance and its
relation to food hypersensitivities. J. Allergy Clin.
Immunol. 115, 312; quiz 13 (2005).
60. Mingrone, G. & Castagneto-Gissey, L.
Mechanisms of early improvement/resolution of
type2 diabetes after bariatric surgery. Diabetes
Metab. 35, 518523 (2009).
61. Clment, K. Bariatric surgery, adipose tissue and
gut microbiota. Int. J. Obes. (Lond.) 35 (Suppl. 3),
S7S15 (2011).
62. Furet, J.P. etal. Differential adaptation of human
gut microbiota to bariatric surgery-induced
weight loss: links with metabolic and low-grade
inflammation markers. Diabetes 59, 30493057
(2010).
63. Delzenne, N.M., Neyrinck, A.M., Backhed, F. &
Cani, P.D. Targeting gut microbiota in obesity:
effects of prebiotics and probiotics. Nat. Rev.
Endocrinol. 7, 639646 (2011).
64. Cani, P.D. & Delzenne, N.M. The gut microbiome
as therapeutic target. Pharmacol. Ther. 130,
202212 (2011).
65. Sultan, A. etal. Tcell-mediated inflammation in
adipose tissue does not cause insulin
resistance in hyperlipidemic mice. Circ. Res.
104, 961968 (2009).
66. Lee, Y.S. etal. Inflammation is necessary for
long-term but not short-term high-fat diet-induced
insulin resistance. Diabetes 60, 24742483
(2011).
67. Thewissen, M.M. etal. Abdominal fat mass is
associated with adaptive immune activation:
theCODAM Study. Obesity (Silver Spring) 19,
16901698 (2011).
68. Viardot, A., Grey, S.T., Mackay, F. & Chisholm, D.
Potential antiinflammatory role of insulin via the
preferential polarization of effector Tcells toward
a T helper 2 phenotype. Endocrinology 148,
346353 (2007).
69. Viardot, A., Lord, R.V. & Samaras, K. The effects
of weight loss and gastric banding on the innate
and adaptive immune system in type2 diabetes
and prediabetes. J. Clin. Endocrinol. Metab. 95,
28452850.
70. Jagannathan-Bogdan, M. etal. Elevated
proinflammatory cytokine production by a
skewed Tcell compartment requires monocytes
and promotes inflammation in type2 diabetes.
J.Immunol. 186, 11621172.
71. Surendar, J., Mohan, V., Rao, M.M., Babu, S. &
Aravindhan, V. Increased levels of both T
H
1 and
T
H
2 cytokines in subjects with metabolic
syndrome (CURES-103). Diabetes Technol. Ther.
13, 477482 (2011).
72. Liu, Z., Stanojevic, V., Avadhani, S., Yano, T. &
Habener, J.F. Stromal cell-derived factor-1
(SDF-1)/chemokine (C-X-C motif) receptor 4
(CXCR4) axis activation induces intra-islet
glucagon-like peptide-1 (GLP-1) production and
enhances cell survival. Diabetologia 54,
20672076 (2011).
73. Kang, K. etal. Adipocyte-derived Th2 cytokines
and myeloid PPAR regulate macrophage
polarization and insulin sensitivity. Cell. Metab.
7, 485495 (2008).
74. Wellen, K.E. & Hotamisligil, G.S. Inflammation,
stress, and diabetes. J. Clin. Invest. 115,
11111119 (2005).
75. Arkan, M.C. etal. IKK- links inflammation to
obesity-induced insulin resistance. Nat. Med. 11,
191198 (2005).
76. Hirosumi, J. etal. A central role for JNK in obesity
and insulin resistance. Nature 420, 333336
(2002).
77. Coletta, D.K. & Mandarino, L.J. Mitochondrial
dysfunction and insulin resistance from the
outside in: extracellular matrix, the cytoskeleton,
and mitochondria. Am. J. Physiol. Endocrinol.
Metab. 301, E749E755 (2011).
78. Clynes, R. Bcell therapy is -tested: Rituximab
puts a pause on -cell destruction. Islets 2,
130132 (2010).
79. Scott, D.L., Wolfe, F. & Huizinga, T.W. Rheumatoid
arthritis. Lancet 376, 10941098 (2010).
80. Kanakasabai, S. etal. Peroxisome proliferator-
activated receptor delta agonists inhibit T helper
type1 (Th1) and Th17 responses in
experimental allergic encephalomyelitis.
Immunology 130, 572588 (2010).
81. Miller, A.M. etal. Interleukin-33 induces protective
effects in adipose tissue inflammation during
obesity in mice. Circ. Res. 107, 650658 (2010).
82. Kowalski, G.M. etal. Deficiency of
haematopoietic-cell-derived IL-10 does not
exacerbate high-fat-diet-induced inflammation or
insulin resistance in mice. Diabetologia 54,
888899 (2011).
83. Hong, E.G. etal. Interleukin-10 prevents diet-
induced insulin resistance by attenuating
macrophage and cytokine response in skeletal
muscle. Diabetes 58, 25252535 (2009).
84. Deiuliis, J.A., Kampfrath, T., Ying, Z., Maiseyeu,A.
& Rajagopalan, S. Lipoic acid attenuates innate
immune infiltration and activation in the visceral
adipose tissue of obese insulin resistant mice.
Lipids 46, 10211032 (2011).
85. Bruun, J.M., Helge, J.W., Richelsen, B. &
Stallknecht, B. Diet and exercise reduce low-
grade inflammation and macrophage infiltration
in adipose tissue but not in skeletal muscle in
severely obese subjects. Am. J. Physiol.
Endocrinol. Metab. 290, E961E967 (2006).
86. Klting, N. etal. Insulin-sensitive obesity. Am. J.
Physiol. Endocrinol. Metab. 299, E506E515
(2010).
87. Cancello, R. etal. Reduction of macrophage
infiltration and chemoattractant gene expression
changes in white adipose tissue of morbidly
obese subjects after surgery-induced weight
loss. Diabetes 54, 22772286 (2005).
88. Wu, D. etal. Eosinophils sustain adipose
alternatively activated macrophages associated
with glucose homeostasis. Science 332,
243247 (2011).
Author contributions
H. Sell and C. Habich contributed equally to all
aspects of this manuscript. J. Eckel contributed to
discussions of content, writing and editing of the
manuscript before submission.
REVIEWS
2012 Macmillan Publishers Limited. All rights reserved