ARTICLE
Auteur(s) : Jean-Philippe
Bastard1, Mustapha Maachi1, Claire
Lagathu1, Min Ji Kim1, Martine
Caron1, Hubert Vidal2, Jacqueline
Capeau1, Bruno Feve3
1Inserm U680, Faculté de Médecine Pierre et Marie
Curie, site Saint-Antoine, Université Pierre et Marie Curie, Paris
6 et Service de Biochimie et Hormonologie, Hôpital Tenon, AP-HP, 4
rue de la Chine, 75970 Paris cedex 20, France
2UMR Inserm-U449; INRA U-1235; Faculté de Médecine R.
Laennec, Université Claude Bernard-Lyon1, 69372 Lyon Cedex 08,
France
3Inserm U693, Université Paris 11 et service
d’Endocrinologie, CHU de Bicêtre, 63 rue Gabriel Péri, 94270 Le
Kremlin-Bicêtre, France
accepté le 26 Janvier 2006
It is now well established that obesity is an independent risk
factor for type 2 diabetes, dyslipidemia, and cardiovascular
diseases (CVD). There is also strong evidence that, for a given
adiposity, there is a large heterogeneity in the metabolic and
cardiovascular risk mainly linked to the location of excessive
adipose tissue. Visceral adipose tissue accumulation is an
important predictive factor of lipid, glucose or atherogenic
disturbances, while location of adipose tissue in the lower part of
the body is not associated with increased alterations at the
metabolic level. Since the description of the metabolic syndrome in
the eighties by Reaven [1], the awareness of its deleterious
consequences and the dramatic rise in the prevalence of obesity led
physicians and public health services to consider it the major
health problem linked to related morbidities.This review will
mainly focus on the mechanisms by which excess adipose tissue can
lead to insulin resistance and type 2 diabetes, and promote the
onset of CVD.A recent and striking discovery is that obesity is
associated with a low-grade inflammation process in adipose tissue,
the pathophysiological mechanisms of which remained poorly
understood, underlining the relationship between fat cells and the
immune system. Another physiological and pathological aspect that
has generated a considerable sum of experimental and clinical work
during the last decade is that adipocytes have the capacity to
synthesize and secrete several factors collectively called
adipokines. Some of them appear to play an important role in
obesity-associated insulin resistance and cardiovascular
complications [2, 3].Therefore, it must also be kept in mind that
at the tissue level, obesity is not an exclusively adipocyte
disease, but also involves other cell types that reside in WAT.
This concept helps us to understand the pathophysiological
mechanisms at the root of insulin resistance and type 2 diabetes.
Adipose tissue inflammation during obesity: a link with
components of the metabolic syndrome
Obesity is associated with a chronic inflammatory response,
characterized by abnormal adipokine production, and the activation
of some pro-inflammatory signalling pathways, resulting in the
induction of several biological markers of inflammation [4-9].
Conversely, a reduction in body weight is accompanied by a decrease
or even a normalization of these biological parameters [10-13].
This association is meaningful, and several animal models suggest
that these inflammatory processes have a causal relationship with
obesity and its co-morbidities such as insulin resistance, type 2
diabetes and CVD.
The role of fat cells in metabolic dysfunctions has long been
considered, but their potential role in an inflammatory process is
a new concept. However, recently, several findings have converged
to indicate that adipocytes share with immune cells certain
properties such as complement activation [14] and pro-inflammatory
cytokine production [4]. Fat cell precursors also share features
with macrophages. Preadipocytes have the capacity for phagocytosis
in response to several stimuli [15, 16]. Moreover, numerous genes
that code for transcription factors, cytokines, inflammatory
signalling molecules, and fatty acid transporters are essential for
adipocyte biology, and are also expressed and functional in
macrophages [17-19].
A body of evidence suggests the presence of an overall,
low-grade inflammation in obesity, with altered levels of several
circulating factors such as an increase in the plasma levels of
C-reactive protein (CRP), tumor necrosis factor-α (TNF-α),
interleukin-6 (IL-6), and other biological markers of inflammation
[2, 3, 20-25]. In addition, there is a correlation in healthy
individuals between body mass index (BMI) and CRP levels [20]. IL-6
has been reported to increase liver CRP production [20, 26].
Interestingly, adipose tissue IL-6 content is higher in obese
patients displaying an increased CRP level. Otherwise, there is at
least a two-fold higher risk of type 2 diabetes within 3-4 years in
obese individuals with higher CRP levels [27].
At the adipose tissue level, TNF-α has been shown to be
over-expressed in WAT from different animal models of obesity, and
is considered to be a molecule that makes a link between
inflammation and obesity. Recombinant TNF-α decreases insulin
sensitivity, while TNF-α- or TNF-α receptor-null mice have an
increased sensitivity in response to this hormone [4, 28]. Thus it
is likely that overproduction of TNF-α by WAT from obese animal
models contributes to insulin resistance.
Other adipose-specific molecules that are involved in the
control of energy metabolism, also regulate immune responses. For
example leptin, in addition to its key role in food intake and
energy expenditure also regulates immune processes.
Leptin-deficient mice or humans display an altered immune status
[29-31]. The reduction in leptin levels could be responsible for
fast-associated immunosuppression [32].
Adipose tissue macrophage infiltration during obesity
Large-scale studies of gene expression using micro-array approaches
have already highlighted that in WAT from rodent genetic models of
obesity the expression of genes coding for proteins involved in
inflammatory processes was markedly altered [33]. Unexpectedly, it
was observed that these variations in gene expression in WAT were
essentially related to a macrophage infiltration in WAT of these
obese mice [34, 35]. These locally present macrophages are
responsible for the major part of the locally-produced TNF-α, and
for an important part of the production of IL-6 and inducible
nitric oxide synthase (iNOS) [34]. This macrophage infiltration has
also been reported in WAT of obese patients [34, 36-40].
It is noteworthy that a reduction in body weight is accompanied,
not only by an improvement in the inflammatory process and the
co-morbidities, but also by a decrease in the expression of genes
coding for inflammation proteins [37]. This phenomenon is already
detectable with a small decrease in body weight. Three months
following by-pass surgery, there is a significant decrease in both
macrophage infiltration and in the steady state levels for mRNA
involved in the inflammatory response [38]. Thiazolidinediones are
able to reproduce this kind of effect on WAT gene expression
[35].
This increase in macrophage infiltration could represent the
cause and/or the consequence of the low-grade inflammation state
associated with obesity [41, 42]. The cellular and molecular
mechanisms responsible for this macrophage infiltration remain
largely unknown. Although it has been suggested that macrophages
present within WAT could derive from preadipocytes [16, 43], some
experiments have shown that macrophages probably originate mostly
from bone marrow precursors [34]. Leptin could promote macrophage
diapedesis from blood flow to WAT [39]. The fat cell is also able
to synthesize and secrete a chemokine, MCP-1 (monocyte
chemoattractant protein-1), a recruiting factor for circulating
monocytes that is over-expressed in obesity [44]. It has been
proposed that factors secreted by the human, hypertrophied, mature
adipocyte can activate endothelial cells present in WAT. In turn,
endothelial cells can favour monocyte adhesion and transmigration
leading to macrophage infiltration [39, 45].
It is now generally considered that both over-production of
pro-inflammatory cytokines by WAT from obese animals or humans
(especially by macrophages that reside in WAT), and the deficiency
in anti-inflammatory adipokines could be involved in the
pathophysiology of insulin resistance.
Adipokines, inflammation and insulin resistance
The name of adipokine is nowadays generally given to any protein
that can be synthesized and secreted by adipocytes (figures 1 and
2)[46]. Several studies have shown that adipokine production is
altered in obesity, type 2 diabetes and metabolic syndrome. This is
observed for leptin, TNF-α, IL-6, adiponectin and resistin and will
be more extensively discussed in this review. Other adipokines such
as angiotensinogen, PAI-1 or the recently discovered visfatin are
also important players in vessel and metabolism regulation but will
not be discussed here.
Leptin
Leptin, is the product of the ob gene. It is involved in the
regulation of energy homeostasis [47] and is almost exclusively
expressed and produced by WAT and more particularly by
differentiated mature adipocytes [48]. Circulating levels [49] and
adipose tissue mRNA expression of leptin [50] are strongly
associated with BMI and fat mass in obesity. Thus, leptin appears
as a real marker of adipose tissue mass in lean humans where the
subcutaneous fraction represents about 80 % of total fat.
Indeed, leptin mRNA expression is higher in subcutaneous adipose
tissue (SAT) than in visceral adipose tissue (VAT) in human [51].
Although leptin acts mainly at the level of the central nervous
system to regulate food intake and energy expenditure, there is a
relationship between leptin and the low-grade inflammatory state in
obesity, suggesting that leptin could exert peripheral biological
effects as a function of its cytokine-like structure [48]. Indeed,
leptin receptors belong to the cytokine class I receptor family,
and several published works have reported that there is an
increased inflammatory response associated with the presence of
hyperleptinemia without obesity [52, 53], and that leptin is able
to control TNF-α production and activation by macrophages [52].
However, the underlying mechanisms have not been clearly
identified.
TNF-α
TNF-α is a pro-inflammatory cytokine produced by a variety of
cell-types, but mainly by macrophages and lymphocytes. It can be
produced by adipose tissue although this production is weak in
humans. Nonetheless, TNF-α is thought to play a major role in the
pathophysiology of insulin resistance in rodents [4] through the
phosphorylation of the insulin receptor substrate-1 (IRS-1) protein
on serine residues. This could prevent its interaction with the
insulin receptor beta subunit, and stop the insulin signalling
pathway. Although clinical studies have shown that VAT is closely
linked to insulin resistance, TNF-α mRNA expression was similar in
SAT and VAT [54, 55].
Moreover, TNF-α is weakly expressed either in subcutaneous or in
deep human adipose tissue depots and this expression is not always
modified in obesity [56]. This corresponds with the evaluation of
in vivo secretion, which showed that TNF-α production by
subcutaneous abdominal adipose tissue was quantitatively negligible
in lean and obese subjects [57]. This suggests that adipose tissue
is not directly implicated in the increased circulating TNF-α
levels observed in obesity in human. It can be hypothesized that
other mechanisms involving a systemic effect of leptin or of other
adipokines may induce TNF-α secretion by other cell types such as
macrophages. Nevertheless, the precise role of TNF-α in human
obesity requires further investigation.
Interleukin-6
Interleukin-6 is produced by many cell types (fibroblasts,
endothelial cells, monocytes), and many tissues including adipose
tissue. It is now well known that IL-6 production by adipose tissue
is enhanced in obesity [5, 6]. It is thought that 15 to 30 %
of circulating IL-6 levels derives from adipose tissue production
in the absence of an acute inflammation [57]. Secretion is higher
in VAT than in SAT [5, 58]. Accordingly, IL-6 mRNA expression is
higher in VAT than in SAT [5]. However, in adipose tissue, the
greater proportion of IL-6 is not produced by mature adipocytes but
rather by cells of the stroma vascular fraction including
preadipocytes, endothelial cells and monocytes-macrophages [5, 58].
Interleukin-6 is a multifunctional cytokine acting on many cells
and tissues. One of the main effects of IL-6 is the induction of
hepatic CRP production, which is now known to be an independent,
major risk marker of cardiovascular complications [59].
Interestingly, there is a strong relationship between IL-6 protein
content in adipose tissue and circulating levels of both IL-6 and
CRP [60]. In addition, IL-6 has been recently proposed to play a
central role in the link between obesity, inflammation and coronary
heart diseases [61]. As VAT can produce higher IL-6 amounts than
SAT [5], this could partly explain the relationship between central
fat depots and cardiovascular risk complications in human.
Moreover, IL-6 production by adipose tissue could directly affect
liver metabolism by inducing VLDL secretion and
hypertriglyceridaemia, since the VAT is closely connected to the
liver by the venous portal system [62].
Recent studies have suggested that IL-6 could be involved in
insulin resistance and its complications [6, 63]. The IL-6 receptor
belongs to the cytokine class I receptor family involving JAK/STATs
(Janus kinases/signal transducers and activators of transcription)
signal transduction pathway [64]. Janus kinase activation induces
STAT phosphorylation, dimerisation and translocation to the nucleus
to regulate target gene transcription [64]. It is now clearly
established that a strong interaction occurs between cytokine and
insulin signalling pathways, and generally leads to an impaired
biological effect of insulin. Although the exact mechanisms have
not yet been clearly elucidated, it could involve tyrosine
phosphatase activation [65] or an interaction between suppressor of
cytokine signalling (SOCS) proteins and the insulin receptor
[66-68]. Whatever the mechanisms involved, it has now been clearly
demonstrated that cytokines such as TNF-α and IL-6 are able to
decrease insulin action [65-70]. Therefore, in addition to the
aggravation of the cardiovascular risk linked to inflammation, the
chronic increase in circulating cytokine levels could contribute to
insulin resistance.
Adiponectin
Adiponectin, having been discovered by several groups, has been
attributed several different names: ACRP30 (adipocyte
complement-related protein of 30 kDa) or adipoQ in mouse and GBP28
(gelatin-binding protein 28) or APM1 (adipose most abundant gene
transcript 1) in human [71]. It is highly expressed in adipose
tissue. Plasma levels of adiponectin, which constitutes 0.01% of
circulating proteins, are between 5 to 30 mg/L in lean control
subjects while those of leptin are between 2 to 8 μg/L. The
expression of adiponectin mRNA is dependent on the adipose tissue
localisation. It is lower in VAT than in SAT [72].
Adiponectin has several particularities which distinguished it
from others adipokines: 1) circulating adiponectin levels are
decreased in obese and/or type 2 diabetic patients and in patients
with coronary heart diseases, 2) there is a strong positive
correlation between adiponectinemia and insulin sensitivity, 3)
there is an inverse correlation between adiponectinemia and obesity
and more particularly with abdominal obesity and 4) adiponectin may
play a protective role against atherosclerosis and insulin
resistance. The insulin-sensitive action of adiponectin may involve
the activation of AMP activated protein kinase (AMPK), which is
known to regulate cellular malonyl CoA concentrations by inhibiting
acetyl CoA carboxylase [73]. This inhibition results in a decreased
level of intra-cellular malonyl CoA and a subsequent decreased
lipogenesis associated with increased mitochondrial fatty acid
beta-oxidation. Adiponectin is also able to regulate liver glucose
production by lowering mRNA expression of phosphoenolpyruvate
carboxykinase and glucose-6-phosphatase, two key enzymes of
neoglucogenesis [71].
In addition to its insulin-sensitising effects, adiponectin may
have a protective effect on the vascular wall by acting early at
several steps of the atherogenesis process: 1) modulation of
endothelial adhesion molecules [74], 2) transformation of
macrophages into foam cells [75] and 3) modulation of vascular
smooth muscle cells proliferation [76]. Moreover, adiponectin may
modulate the TNF-α-induced inflammatory response, since it has been
shown that adiponectin reduces TNF-α secretion of macrophages [77].
This anti-TNF-α effect may partly explain the anti-inflammatory and
anti-atherogenic effect of adiponectin. By contrast both TNF-α and
IL-6 reduce human adipocyte mRNA expression of adiponectin [78],
which is an additional mechanism by which these two cytokines
induce insulin resistance.
Two adiponectin receptors, adipoR1 and adipoR2, localized on
chromosomes 1q32 and 12p13 respectively, have been recently cloned
[79]. AdipoR1 is predominantly expressed in skeletal muscle while
adipoR2 is mainly expressed in the liver. However, the
physiological relevance and the transduction signal pathways of
these two receptors remain to be determined.
Resistin
Steppan et al. have recently discovered resistin, also called FIZZ3
(found in inflammatory zones) or adipocyte secreted factor (ADSF)
while looking for new molecular targets of thiazolidinediones in
adipocytes [80]. They showed that circulating and adipose tissue
resistin levels were increased in obese rodents but decreased under
treatment with thiazolidinediones. Moreover, infusion of
recombinant resistin into lean control animals induced insulin
resistance, while its immuno-neutralisation improved insulin
sensitivity in insulin-resistant obese animals.
In cultured adipocytes, resistin reduced insulin-stimulated
glucose transport, an effect which was reversed using an
anti-resistin antibody. In addition, resistin inhibited adipocyte
differentiation [81]. These studies suggest that resistin could be
a link between adipose tissue, obesity and insulin resistance.
However, additional, contradictory studies have indicated a
decreased mRNA gene expression in adipose tissue from various
insulin-resistant rodent models. Nevertheless, recombinant resistin
caused major liver insulin resistance [82].
It was recently shown that resistin-knockout mice have lower
fasting glycaemia and increased glucose tolerance and insulin
sensitivity associated with a reduced liver glucose production
[82]. The lack of resistin could lead to the activation of AMPK and
consequently to a decreased expression of genes involved in liver
neoglucogenesis, suggesting that resistin could exert effects
opposite to those of adiponectin. Finally, resistin-knockout mice
under a high fat diet regimen became as obese and insulin-resistant
as their wild type counterparts. However, fasting glycaemia was
lower in resistin-knockout mice, suggesting the implication of
resistin in the hyperglycaemia and insulin resistance observed in
obesity.
With regards to resistin in humans, several discrepancies have
been observed since some studies have shown that adipose tissue
expresses resistin while others did not find its presence or
detected only very low mRNA expression in this tissue. It is
believed that the adipocyte is not the major cell type producing
resistin in humans, which rather is produced by circulating
monocytes and macrophages [82]. Finally, most of the studies found
no correlation between plasma resistin levels, BMI and insulin
resistance in human. Nonetheless, the macrophage localization of
resistin and its inter-relationship with adipocyte metabolism and
function are currently under investigation.
Inflammatory pathways in insulin resistance and type 2
diabetes
A century ago, it was suggested that inflammation could be involved
in the pathophysiology of type 2 diabetes [83]. Although the
molecular mechanisms involved are not clearly understood, it has
been suggested that not only the pro-inflammatory effects of
cytokines, but also of reactive oxygen species and free fatty acids
in obesity are mediated through specific intracellular signalling
pathways, involving the nuclear factor (NF)-κB, IκB kinase, (IKK),
Activating Protein-1 (AP-1) and c-Jun NH2-terminal
kinase (JNK) signalling molecules. All these pathways could
interact with insulin signalling via serine/threonine inhibitory
phosphorylation of IRS.
Genetic or pharmacological manipulations of these different
effectors of the inflammatory response modulate insulin sensitivity
in different animal models. Indeed, invalidation of these genes,
which mediate inflammatory responses, modulates insulin
sensitivity. Heterozygous IKK-β+/- mice under high fat
diet regimen or mated with ob/ob obese mice have lower glycaemia,
an improvement in insulin sensitivity and insulin signalling as
compared to IKK-β+/+ mice [84, 85].
By contrast, tissue-specific, over-expression of IKK-β in liver
and adipose tissue but not in skeletal muscle leads to systemic
insulin resistance. Accordingly, selective inhibition of the NF-κB
function in liver and adipose tissue protects against insulin
resistance in nutritional and genetic animal models of obesity
[86].
JNK activity, which is mainly related to the JNK1 isoform, is
increased in obese mice. In response to a high fat diet or in the
context of genetically obese rodents, JNK1-null animals gain less
body weight and are less prone to altered insulin sensitivity [87].
Liver-specific down-regulation of JNK signalling improves insulin
responsiveness in animal models of type 2 diabetes [88].
The implication of inflammation pathways is also suggested by
the protective effect of some anti-inflammatory compounds against
obesity-associated insulin resistance. Aspirin not only inhibits
IKK and JNK pathways [89, 90], but also other serine/threonine
kinases involved in TNF-α-induced insulin resistance. In addition,
through its antioxidant properties, aspirin decreases NF-κB and
AP-1 activation in response to oxidative stress [90]. Salicylate
reduces the severe insulin resistance observed in genetically obese
rodents [84]. In human species, high doses of salicylate improve
insulin sensitivity of type 2 diabetic patients [91]. Nevertheless,
the exact mechanisms by which aspirin modulates carbohydrate
metabolism and insulin sensitivity remain to be investigated
[92].
Other drugs with well characterized anti-inflammatory effects,
such as thiazolidinediones and statins, also possess anti-diabetic
properties. Thiazolidinediones have an insulin-sensitizing action
that is possibly related, at least in part, to their ability to
decrease adipocyte TNF-α production, or TNF-α effects on several
target tissues, and by contrast to induce adiponectin expression
[93]. Statins modulate endothelial functions and trans-endothelial
leukocyte migration, inhibit pro-inflammatory cytokine secretion
and interfere in the NF-κB pathway [94]. Accordingly, pravastatin
is known to reduce the risk of type 2 diabetes.
Conclusion
During the last decade, understanding of the biology of adipose
tissue and, in particular, its secretory functions have
dramatically improved, and this has completely modified our
understanding of the pathophysiological link between the increase
of fat mass, namely obesity, insulin resistance and cardiovascular
complications. The adipokines produced by adipocytes or by adipose
tissue-infiltrating macrophages, are able to induce a low-grade
inflammation state that could play a central role in obesity and
type 2 diabetes-related insulin resistance and cardiovascular
complications. New therapeutic approaches can thus be considered.
However, further studies are necessary to better understand the
regulation and biological functions of adipokines. New adipokines
will be certainly discovered in the next few years, which will lead
us to greater appreciation of the complexity of the cross-talk
between metabolic tissues, and their alteration in human diseases.
Acknowledgements
This work was supported by grants from INSERM and Universities
Pierre et Marie Curie, Paris VI and Paris XI.
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