Macrophage infiltration and cytokine release in adipose tissue:
angiogenesis or inflammation?
Lindsay E. Wu•Samantha L. Hocking•
David E. James
Received: 31 May 2010/Accepted: 13 July 2010/Published online: 10 September 2010
? The Japan Diabetes Society 2010
infiltrated by macrophages triggered the concept that type 2
diabetes is a low-grade inflammatory disease. In this
review, we re-evaluate the role of macrophage infiltration,
TNFa secretion and IKKb/JNK signalling in insulin
resistance, and put forward the hypothesis that these
intermediates are important mediators of adipose tissue
angiogenesis. Expansion of adipose tissue vasculature is
essential to support adipose tissue growth during devel-
opment and adipose tissue expansion in adulthood. We
propose that a major role of so-called pro-inflammatory
adipokines is to stimulate adipose tissue angiogenesis to
support the nutrient requirements of expanding fat depots.
Inhibition of angiogenesis overrides insulin resistance and
obesity not by blocking the peripheral effects of the
inflammatory pathway on insulin resistance, but rather by
central effects on food intake. This unveils a possible
feedback loop involving adipose angiogenesis and central
regulation of food intake that is independent of a classical
The observation that obese adipose tissue was
Adipose tissue ? Insulin resistance ? Adipokines
Angiogenesis ? Macrophages ? Inflammation ?
Role of adipose tissue in metabolic health and disease
It has become apparent that adipose tissue plays an
essential role in the pathogenesis of metabolic disease.
However, pinpointing the precise mechanism for this effect
has been difficult. For instance, while it is clear that obesity
is associated with metabolic disease, there is a subset of
individuals for whom obesity would appear not to be a risk
at all . Conversely, lipodystrophy, a rare condition
typified by lack of adipose tissue, is strongly associated
with type 2 diabetes . Paradoxically, in some circum-
stances expansion of fat depots as in the case of the
globular adiponectin transgenic ob/ob mouse  or treat-
ment with thiazolidinediones (TZDs)  leads to an
improvement in metabolic status. A consensus view that
essentially unifies these observations is that whenever the
capacity of the adipose reservoir to store fat is exceeded,
lipotoxicity may occurin
Exceeding the normal storage capacity of adipose tissue
through increased caloric intake or lipodystrophy leads to
lipid overflow, leading to lipotoxicity and its associated
pathologies, such as insulin resistance. Potential lipotox-
icity may be overcome by expanding adipose mass, which
seems to be part of the restorative mechanism of TZDs .
But how does excess lipid cause insulin resistance and type
2 diabetes? Several models have been proposed, and these
include the portal hypothesis, ectopic lipid hypothesis and
Model 1: visceral adipose tissue and the portal
The portal model arose from the epidemiological associa-
tion between visceral adiposity and insulin resistance
[6, 7]. Under this model, increased visceral adipose tissue
L. E. Wu and S. L. Hocking contributed equally to this work.
L. E. Wu ? S. L. Hocking ? D. E. James (&)
Diabetes and Obesity Program, Garvan Institute of Medical
Research, 384 Victoria St, Darlinghurst, NSW 2010, Australia
Diabetol Int (2010) 1:26–34
leads to a rise in portal vein plasma free fatty acid con-
centrations, leading to an accumulation of lipid interme-
diates in hepatocytes, which in turn cause hepatic insulin
resistance [6, 8]. A limitation of this model is that it is not
clear how hepatic insulin resistance leads to insulin resis-
tance in muscle and adipose tissue, as there is still no solid
evidence that there is a temporal segregation in the onset of
insulin resistance in different tissues.
Model 2: ectopic lipid hypothesis
An alternate and related model is that insufficient adipose
storage results in ectopic deposition of lipid in all insulin
sensitive tissues, resulting in global insulin resistance .
In this model, blame may lie with a lack of adipose tissue
in general, with expansion of visceral fat somehow signi-
fying an adipose tissue storage crisis, rather than an
intrinsic fault with visceral adipose tissue. TZDs are among
the most effective anti-diabetic agents in clinical use, and it
is thought that they exert their effects at least in part
through the increase in adipose tissue mass that they
stimulate . This increase in fat mass may assist in
partitioning lipids away from other tissues such as liver
and muscle, thereby reducing lipotoxicity and insulin
Model 3: endocrine hypothesis
The third model, which also implicates the fat cell as the
culprit, relates to the observation that adipose tissue
secretes a range of factors called adipokines . These
may be either beneficial or detrimental to the metabolic
state of the animal. For example, the discovery almost
20 years ago that adipose tissue in obese rodents and
humans expressed TNFa  promoted the now widely
held view that adipose tissue in obesity is pro-inflammatory
. Subsequently, it was found that other peptide hor-
mones, collectively termed adipokines, were expressed in
adipose tissue, and many allegedly control whole body
metabolism via mechanisms that intersect with the immune
system. Other adipokines, such as leptin, have a more
direct effect on metabolism by modulating central regula-
tion of food intake by direct interaction with receptors in
the hypothalamus, launching the fat cell as a major
peripheral regulator of brain function . This has led to
the endocrine model, in which obesity causes a shift in the
production of adipokines towards a more pro-inflammatory
state, resulting in insulin resistance both locally within
adipose tissue and via endocrine interactions to create
systemic insulin resistance. Indeed, there is a convergence
of thinking proposing that excess circulating lipids (Model
2) primes the pro-inflammatory response in fat escalating
this cascade of events. This latter model has received
widespread and mounting support over the past 5 years,
and it is now widely held that diabetes is a disease of the
immune system .
Model 4: adipose tissue angiogenesis
The use of lipodystrophic mouse models [15–17] to study
the role of the expanding adipose mass in metabolic disease
has led to the view that insufficient capacity under condi-
tions of unrestricted access to food will lead to disease due
to ectopic lipid deposition and lipotoxicity. In contrast to
this consensus view, reduction of adipose tissue expansion
through inhibition of adipose-specific angiogenesis leads to
a different conclusion regarding the role of fat expansion
during metabolic disease . Adipose tissue, unlike most
other adult tissues, can expand and regress throughout
adulthood. This requires an increase in the volume and/or
number of adipocytes as well as alterations in the sur-
rounding connective tissue matrix and vasculature. On face
value, one might have expected that strategies designed to
block adipose tissue angiogenesis might have phenocopied
lipodystrophic models. Unexpectedly, administration of
anti-angiogenic agents to mice from different obesity
models resulted in dose-dependent weight reduction and
adipose tissue loss [19, 20]. Targeting of a pro-apoptotic
peptide to the adipose tissue vasculature similarly causes a
reduction in fat mass . Extraordinarily, the reason for
reduced fat mass in these animals appears to be linked to
reduced appetite, as these animals consumed approxi-
mately 30% less energy during high fat feeding . This
has given rise to the concept that there is an intricate link
between adipose blood supply and food intake. Adipose
tissue development during embryogenesis is spatially and
temporally associated with microvessel growth, with
angiogenesis often preceding adipogenesis . Adipo-
cytes and endothelial cells may share a common progenitor
that can trans-differentiate into mature adipocytes or
endothelial cells depending on the differentiation condi-
tions it is exposed to . Pre-adipocytes can influence
proliferation and reduce apoptosis in mature endothelial
cells  and conversely, endothelial cell-conditioned
media promotethe proliferation
capacity of pre-adipocytes in vitro . The exact mech-
anisms governing the coordinated expansion of adipose
tissue and its microvasculature remain unresolved. We
propose that purported inflammation in adipose tissue is an
adaptive response to promote adipose tissue angiogenesis
to meet the requirements of expanding adipose tissue
depots rather than a maladaptive response in obesity.
Remarkably, in direct contrast to lipodystrophy models,
reduction of adipose tissue by elimination of adipose vas-
culature improves insulin sensitivity, even when the animal
is challenged with high fat feeding [18, 20, 21]. This
Role of angiogenesis in obesity 27
paradoxical improvement in insulin sensitivity despite
reduced adipose tissue mass is mediated by reduced food
intake . Treatment of mice with the general angio-
genesis inhibitor TNP-470 decreased food intake in two
separate studies [20, 78]. Likewise, exogenous adminis-
tration of the anti-angiogenic cytokine angiostatin decrea-
ses food intake . Genomic deletion of c-Jun N-terminal
kinase (JNK), which is required for angiogenesis [64, 65],
results in a small but significant decrease in food intake
. Targeted apoptosis of adipose tissue vasculature with
a pro-apoptotic peptide leads to a significant reduction in
food intake, independently of leptin, neuropeptide Y and
Agouti-related protein levels . These data support the
presence of direct neural communication between the
centres in the brain, which control appetite and hunger, and
the adipose tissue vasculature. This may represent another
adipose tissue-brain-adipose tissue neural circuit that
functions independently of leptin. Autonomic nerves and
microvasculature in adipose tissue are intimately related
[26, 27], and it is conceivable that regression of adipose
tissue vasculature by endothelial apoptosis confers a par-
acrine interaction between microvasculature and nerve
cells, functioning to limit food intake via the central ner-
vous system. In the context of shrinking adipose tissue
depots, a reduction in food intake protects the animal from
ectopic storage of lipid in muscle and liver, with its
would otherwise be the inevitable consequence of unbri-
dled caloric intake.
Adipose tissue macrophage infiltration, adipokines,
insulin resistance and angiogenesis
The observations described above offer not only a sobering
view of the link between fat mass per se and insulin
resistance, but may elicit a rethink in the link between
inflammation and insulin resistance in obesity. In the past
few years we have seen more and more examples of the
inextricable link between angiogenesis and inflammation.
A pathological angiogenic response to a wound is often
preceded by an immune response. In this instance the
immune response combats the spread of invasion by for-
eign pathogens. Innate angiogenesis, as might be observed
during obesity, may simply be mistaken as an immune
response. In fact there is much evidence to support this
view. One of the factors that is secreted as part of the
angiogenic response is TNFa , the same factor that is
increased in obese adipose tissue. In the context of angi-
ogenesis, TNFa plays a key role in stimulating local
endothelial cells to aid recruitment of leukocytes and their
differentiation into macrophages as well as in the release of
cytokines such as VEGF and PDGF that play an intimate
role in angiogenesis . While there is some controversy
surrounding this mechanism, recent studies indicate that
the temporal sequence of TNFa activation is important to
the in vivo angiogenic response and that this involves an
intracellular signalling pathway involving JNK, nuclear
factor jB (NFjB) and IjB kinase (IKK) [30–34].
Remarkably, the TNF-JNK-NFjB-IKK signalling pathway
is precisely the same pathway that has been implicated in
the onset of insulin resistance in obesity [35–38].
It has been proposed that adipose tissue macrophage
infiltration plays a key role in mediating insulin resistance
during obesity . In two landmark publications in 2003,
macrophage infiltration into obese adipose tissue was
demonstrated, and it was proposed that this is evidence of
chronic inflammation in adipose tissue [40, 41]. Macro-
phages, not adipocytes, were subsequently found to be the
principal source of TNFa secretion in adipose tissue .
Treatment with the anti-inflammatory salicylate reduces
macrophage infiltration and improves the metabolic phe-
notype , adding weight to the argument that inflam-
mation and insulin resistance are inextricably linked. The
association between chronic inflammation and insulin
resistance is supported by these data; however, the question
remains: why does macrophage infiltration in adipose tis-
sue occur at all?
The dominant viewpoint that macrophages in adipose
tissue are exclusively pro-inflammatory may overlook the
important role macrophages play in angiogenesis .
Macrophages secrete a variety of pro-angiogenic mole-
cules, including PDGF and VEGF [43–45]. In fact, mac-
rophage infiltration may be an essential process needed for
angiogenesis in adipose tissue, due to the abundant secre-
tion of PDGF from macrophages . As discussed above,
the secretory protein for which macrophages are best
known, TNFa, plays a key role in inducing angiogenesis
[28, 29, 47]. Macrophages secrete a variety of other pro-
teins that demonstrate powerful pro-angiogenic effects
including monocyte chemotactic protein 1 (MCP-1) ,
macrophage inhibitory factor  and interleukin-6 (IL-6)
Adipose tissue secretes a range of factors that allegedly
have a broad spectrum of biological actions . Many of
these adipokines are involved in the acute phase response,
and it is assumed that secretion of these proteins from
adipocytes provides the chemotactic signal needed for
macrophage recruitment. MCP-1 is one example . In
addition to macrophage infiltration, MCP-1 also plays an
important role in angiogenesis . It is widely overlooked
that many, if not all, of the acute phase response proteins
secreted from adipocytes also play a role in angiogenesis.
These proteins include haptoglobin [52, 53], orosomucoid
 and macrophage colony-stimulating factor . Adi-
pocytes secrete multiple members of the complement
28 L. E. Wu et al.
pathway . Inhibition of the complement pathway
decreases angiogenesis in an in vivo model . Perhaps
the best known adipokines are leptin and adiponectin, and
these both have potent pro-angiogenic effects [58–63]. A
review of the literature shows a surprising 42 proteins that
are known to be secreted from adipocytes that also have a
demonstrated role in the regulation of angiogenesis
(Tables 1, 2). In addition to these secretory proteins, adi-
pocytes secrete 1-mono-butyro-glycerol, a small molecule
that has potent angiogenic effects . Silverman and co-
workers  showed that adipocyte-conditioned media
could induce gross changes in corneal neovascularisation.
This effect was observed using conditioned media from
adipocytes, but not other cell types, including muscle and
liver. These data provide evidence for the unique angio-
genic properties of adipose tissue and the pro-angiogenic
nature of the adipocyte secretome.
The activation of JNK and IKKb by TNFa in adipocytes
is considered to be the mechanism whereby adipose tissue
inflammation confers insulin resistance . JNK and
IKKb catalyse serine phosphorylation of the key insulin
signalling intermediate IRS-1, which results in its inacti-
vation and degradation [37, 66–69]. This mechanism was
proposed to mediate insulin resistance in insulin-sensitive
tissues [67, 68, 70, 71]; however, subsequent studies have
found that insulin resistance still occurs even when the
insulin signalling pathway is activated downstream of IRS-
1 . Indeed, the most persuasive argument against the
importance of IRS-1 inactivation and degradation by JNK
and IKKb in mediating insulin resistance lies in the
importance of activation of Akt, a central kinase that is
downstream of IRS-1, in mediating insulin-stimulated
glucose uptake and GLUT4 translocation. Activation of as
little as 5% of the total Akt pool is required to achieve
maximal GLUT4 translocation to the PM . In these
circumstances, partial degradation of an upstream adaptor
protein, in this case IRS-1, is unlikely to be of importance
in mediating insulin resistance. Rather than inactivation of
IRS-1 being the sole and primary purpose associated with
activation of the TNFa signalling pathway, IKKb and JNK
signalling in adipocytes may simply be a bystander effect
from macrophage infiltration, which would be required to
stimulate angiogenesis. IKKb has been shown to play an
essential role in angiogenesis, due to its role in mTOR
signalling in the endothelium [32, 33]. Like IKKb, JNK has
also been shown to play a role in angiogenesis, with
pharmacological antagonism of JNK inhibiting angiogen-
esis [30, 31]. The primary goal of macrophage infiltration
Table 1 Pro-angiogenic
secretory proteins secreted from
ATS7_HUMAN A disintegrin and metalloproteinase
with thrombospondin motifs 7
CATB_HUMANCathepsin B 
CATD_HUMAN Cathepsin D 
CO2_HUMAN Complement C2
CO3_HUMAN Complement C3
CFAB_HUMAN Complement factor B
CFAH_HUMAN Complement factor H
EGFR_HUMAN Epidermal growth factor receptor
ECM1_HUMAN Extracellular matrix protein 1
LEP_HUMANLeptin [58, 59]
CSF1_HUMANMacrophage colony-stimulating factor 1 
CD14_HUMANMonocyte differentiation antigen CD14 
PAI1_HUMANPlasminogen activator inhibitor 1 
Role of angiogenesis in obesity 29
and TNFa secretion might be to activate IKKb and JNK in
endothelial cells to stimulate angiogenesis, with IKKb and
JNK signalling to adipocytes a secondary consequence.
Angiogenesis is necessary for adipose tissue expansion
The prominence of angiogenic regulatory molecules
secreted from both adipocytes and adipose tissue macro-
phages is not unexpected due to the unique requirement for
unlimited adipose tissue expansion throughout adult life.
Obesity is one of the few occasions where significant
angiogenesis may be expected in an adult, the others being
pregnancy, tumour growth and mechanical tissue damage.
During obesity, a combination of hypertrophy and hyper-
plasia occurs . In contrast, expansion of other tissues
such as skeletal muscle occurs through hypertrophy only
. During adipose tissue expansion, remodelling of
vascular networks is necessary to supply newly differen-
tiating and hypertrophic adipocytes with oxygen and
nutrients . Indeed, circulating serum levels of angio-
genic regulatory molecules such as VEGF correlate with
obesity  and in particular with visceral obesity .
Macrophage infiltration into adipose tissue may be trig-
gered by hypertrophic adipocytes as macrophage numbers
in adipose tissue, in both rodents and humans, are posi-
tively correlated with adipocyte cell size . Enlarged
adipocytes are known to secrete growth factors that induce
pre-adipocyte proliferation . If adipocytes possess a
limited capacity for hypertrophy, it is possible that once a
critical threshold is reached, adipocytes secrete macro-
phage chemoattractant proteins and other paracrine growth
factors to induce angiogenesis as a necessary prerequisite
for pre-adipocyte hyperplasia.
Most of the evidence supporting a role for inflammation
in obesity and diabetes is based upon the observation that
neutralisation of the ‘immune response’ either pharmaco-
logically or genetically resolves many of the deleterious
effects of obesity including in many cases obesity itself
. The resolution of obesity in these studies inevitably
leads to questions about the true underlying pathophysio-
logical process. For example, salicylate, which as an anti-
inflammatory improves insulin sensitivity, is also an
inhibitor of angiogenesis [35, 42, 79]. It is conceivable that
neutralisation of the immune response could improve
insulin sensitivity; however, a reduction in adiposity would
have to involve either increased energy expenditure or
reduced food intake, yet many of these studies have not
provided a clear explanation for this phenotype [12, 13, 35,
38, 42]. Could it be that neutralisation of so-called pro-
inflammatory proteins such as TNF, JNK, IKK and others
rather elicit a metabo-protective effect via blockade of the
adipose angiogenic response? If this were the case, one
might envisage that, as in the peptide inhibitor studies of
Kolonin and colleagues , these animals lose weight due
to central effects on food intake. Indeed, this has very
recently been shown to be the case . Some, but not all,
of these animal models do exhibit reduced food intake.
More interestingly, it has recently been shown that deletion
of JNK in the brain to a large extent phenocopies the whole
Table 2 Anti-angiogenic
proteins secreted from
ACE_HUMAN Angiotensin-converting enzyme[100, 101]
APOH_HUMAN Beta-2-glycoprotein 1
SODE_HUMAN Extracellular superoxide dismutase
FIBG_HUMAN Fibrinogen gamma chain
TIMP1_HUMAN Metalloproteinase inhibitor 1
NGAL_HUMAN Neutrophil gelatinase-associated lipocalin
PTX3_HUMAN Pentraxin-related protein PTX3
PEDF_HUMAN Pigment epithelium-derived factor
SPA3C_HUMANSerine protease inhibitor A3C 
SAP_HUMAN Sulfated glycoprotein 1
30 L. E. Wu et al.
body JNK knock out—again raising concerns about the
peripheral immune model in diabetes . It should be
noted that while food intake was not reduced in all of these
animal models, this is inherently a difficult parameter to
measure accurately, and even a small but sustained
reduction in food intake could have a major impact on body
weight over the long term.
Adipose tissue inflammation is part of the angiogenic
In conclusion, we propose that the inflammation model of
diabetes and obesity may be a case of mistaken identity. In
response to caloric intake, adipose tissue has a unique
requirement to expand or retract its vasculature in coordi-
nation with adipocyte hypertrophy and hyperplasia. In
order to do this, cytokines and their downstream signalling
molecules, which play a role in both angiogenesis and
inflammation, are upregulated (Fig. 1). It is conceivable
that the production of so-called ‘pro-inflammatory cyto-
kines’ is for the sole purpose of inducing angiogenesis,
given the high degree of cross-over between the angiogenic
and inflammatory pathways. These pathways may well
have co-evolved as part of the wound healing response, and
the same set of molecules may have diverged to regulate
both the inflammatory response as well as the bona fide
appear to be such intimately linked processes that one
could argue that the difference between the two is a matter
of semantics. This still leaves open the question as to
whether the by-products of the angiogenic response,
namely ‘pro-inflammatory cytokines’ such as TNF, could
be perpetrators of metabolic defects including insulin
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