Adipose tissue is a complex organ that comprises a wide range of cell types with diverse energy storage, metabolic regulation, and neuroendocrine and immune functions. Because it contains various immune cells, either adaptive (B and T lymphocytes; such as regulatory T cells) or innate (mostly macrophages and, more recently identified, myeloid-derived suppressor cells), the adipose tissue is now considered as a
Obesity is a growing epidemic worldwide; its prevalence has been rising tremendously over the last 30 years (WHO, 2013). Excess adiposity is an established risk factor for metabolic diseases including insulin resistance, type 2 diabetes (T2D), hypertension, nonalcoholic fatty liver disease (NAFLD), polycystic ovarian diseases, and several types of cancer [
Obesity is a proinflammatory condition in which hypertrophied adipocytes and adipose tissue-resident immune cells (primarily lymphocytes and macrophages) both contribute to increased circulating levels of proinflammatory cytokines. The obesity-associated state of chronic low-grade systemic inflammation, termed “metabolic inflammation,” is considered a focal point in the pathogenesis of insulin resistance and T2D in humans and rodent animal models [
Adipose tissue primary function is to store excess nutrients as triacylglycerols and to release free fatty acids during fasting. A major step forward to the recognition of the major secretory and endocrine role of WAT occurred in the 1990’s with the demonstration that adipocytes synthesize and secrete the proinflammatory cytokine tumor necrosis factor alpha (TNF-
Adipose tissue from lean individuals preferentially secretes anti-inflammatory adipokines such as adiponectin, transforming growth factor beta (TGF
Adipokines enlisted in regulation of insulin resistance are adiponectin, leptin, resistin, visfatin, chemerin, TNF-
Adipokines increased in obesity and/or diabetes (adapted and updated from [
Adipokine | Distribution | Function | Increased in obesity |
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Leptin | Secreted predominantly by WAT, to a lesser degree, in hypothalamus, gastric epithelium, placenta, and gonads | Regulates energy intake, expenditure and feeding behavior. Also regulates storage of fat and insulin signaling | Increased in mouse models of obesity. Increased in human obesity and correlated with BMI and decreased with weight loss |
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Resistin | In rodents, secreted by adipocytes. In humans, secreted predominantly by circulating macrophages and monocytes, to a lesser degree, by WAT | Implicated in glucose metabolism, in the regulation of neoglucogenesis and insulin resistance in rodents. More proinflammatory role in humans | Increased circulating concentrations in mouse models of obesity. Increased in human obesity and correlated with insulin resistance in diabetic patients |
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TNF- |
Expressed by macrophages and adipocytes (visceral WAT > subcutaneous WAT) | Affects insulin and glucose metabolism. Provokes insulin resistance and stimulates lipolysis | Increased in mouse models of obesity. Increased in human obesity and correlated with BMI |
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IL-6 | One-third of total circulating levels are expressed predominantly by adipocytes. Also expressed in macrophages, skeletal muscle, endothelial cells, and fibroblasts | Controversial role in the development of insulin resistance. Affects glucose metabolism | Increased circulating levels in human obese subjects and correlated with adiposity and reduced with weight loss. Increased in plasma of T2D patients |
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IL-7 | Secreted by stromal and vascular endothelial cells | Homeostatic immune cytokine. Also regulates body weight, adipose tissue mass and function, and insulin signaling | Increased in morbidly obese subjects |
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IL-8 | Secreted by adipocytes (visceral WAT > subcutaneous WAT) and macrophages | Neutrophil chemotaxis | Increased in obese subjects and related to fat mass and TNF- |
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IL-1 | Secreted mainly by adipocytes and macrophages | Role in macrophages chemotaxis and thermogenesis | Increased in obese mice. Increased in human obesity and predictive of T2D |
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RBP4 | Secreted by adipocytes, macrophages, and hepatocytes | Affects insulin sensitivity, hepatic glucose output, and muscle insulin signaling | Increased circulating levels in obese subjects and correlated with BMI and insulin resistance |
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MCP-1 | Secreted by adipose tissue | Affects insulin sensitivity and increases macrophage recruitment in adipose tissue and inflammation | Increased in mouse models of obesity. Increased in T2D subjects |
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PAI-1 | Expressed by WAT | Potent inhibitor of fibrinolytic pathway | Increased in human obesity and T2D subjects |
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CXCL5 | Secreted by macrophages within the stromal vascular fraction | Interferes with insulin signaling in muscle | Circulating levels are higher in obese insulin-resistant individuals than in obese insulin-sensitive and decreased after a 4-week period on low-calorie diet |
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Visfatin | Expressed in liver, muscle, WAT, bone marrow, and lymphocytes | Role in insulin sensitivity, insulin secretion and inflammatory properties | Increased in obesity and correlates with visceral adiposity in humans |
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Chemerin | In rodents and humans, expressed in placenta and WAT | Regulates adipocyte development and metabolic function | Increased circulating levels in obese and T2D patients and correlated with body fat, glucose, and lipid metabolism |
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Vaspin | Secreted by WAT, hypothalamus, pancreatic islets, and skin | Improves insulin sensitivity | Increased in obesity and T2D patients |
Adipokines decreased in obesity and/or diabetes (adapted and updated from [
Adipokine | Distribution | Function | Decreased in obesity |
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Adiponectin | Only secreted by adipose tissue. Lower production in men | Insulin sensitizing effect. Improves insulin resistance and glucose metabolism | Decreased in mouse models of obesity. Decreased in human obesity and correlated negatively with BMI. Increased after weight loss |
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IL-10 | Secreted by monocytes, macrophages, dendritic cells, and B and T cells | Improves insulin sensitivity and glucose transport | Attenuated in T2D patients and increased with weight loss |
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Omentin | Expressed in heart, lungs, ovary, and placenta and predominantly produced by WAT | Improve glucose uptake in human adipocytes and has an anti-inflammatory effect | Decreased circulating levels in obese subjects. In impaired glucose tolerant (IGT) and subjects with T2D, circulating levels are lower those when compared with matched controls |
TNF-
A key mechanism by which TNF-
IL-6 is a multifaceted, pleiotropic cytokine that is a central player in the regulation of inflammation, hematopoiesis, immune responses, and host defense mechanisms [
On the other hand, a number of
As stated above, leptin was one of the first proteins shown to be secreted from adipose tissue, through the identification and sequencing of the
Importantly, leptin also plays a key role in controlling immunity and inflammation [
Unlike leptin, the circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are decreased in obesity [
Resistin is another unique adipocyte-derived signaling cysteine-rich molecule that was first identified in obese mice, deriving its name because of its resistance to the action of insulin. In rodents, resistin is secreted primarily from adipose tissue, whereas in humans resistin can be detected in other tissues like placenta, skeletal muscle, small intestine, spleen, stomach, thymus, thyroid gland, and uterus, being predominantly expressed in macrophages [
However, the role of resistin in the development of insulin resistance in humans is not as clear as in rodents. Since resistin is preferentially expressed by macrophages in humans, it suggests a proinflammatory role of resistin rather than a role in regulating glucose metabolism. Resistin mRNA expression level is higher in obese subjects, likely resulting from increased infiltration of macrophages in the adipose tissue. Several studies have reported positive correlations between resistin levels and insulin resistance
During the past decades, IL-7 has been identified as the major homeostatic cytokine supporting the survival of
Without IL-7 the lymphoid system cannot be built and maintained. Interestingly, the role of IL-7 on lymphocyte homeostasis was shown to partly rely on its control of basal lymphocyte glucose metabolism through the expression of the glucose transporter GLUT-1, which promotes glucose uptake and increases metabolic activity as well as cell size [
Recently, we and others identified IL-7 as a new secretory product of the adipose tissue, mostly produced by cells of the stromal vascular fraction [
Strikingly, we showed that IL-7 overexpressing mice presented a lipodystrophy-like phenotype: reduced WAT mass is associated with impaired adipocyte differentiation and intolerance to glucose and insulin resistance, these traits being commonly associated with lipodystrophy in both animals and humans [
The first part of our review showed that the apparent metabolic simplicity of the adipose tissue is illusory; this is also true regarding its cellular composition. Besides lipid-filled mature adipocytes, the tissue is also composed of various stromal cells, including preadipocytes, endothelial cells, fibroblasts, and immune cells [
Obesity is characterized by the accumulation of diverse immune cells in the adipose tissue. Notably, proinflammatory macrophage infiltration and inflammation-related gene expression precede the development of insulin resistance and appear to be a cardinal feature of obesity in rodents and humans [
Adipose tissue macrophages (ATMs) accumulate in both the subcutaneous and visceral expanding fat depots, even though macrophage infiltration appears to be more prominent in the latter [
Similarly to any immune and inflammatory response, macrophage infiltration in the obese adipose tissue results from blood monocyte influx, mainly attracted by the chemokine monocyte chemoattractant protein-1 (MCP-1) which is secreted by hypertrophic adipocytes. It has been reported that MCP-1 secretion is markedly enhanced locally and in plasma of obese rodents and humans [
Kitade et al. recently identified and characterized a critical role for CCR5, another C-C motif chemokine receptor, in the regulation of obesity-induced WAT inflammatory response and insulin resistance [
Alterations in ATM content and polarization state occur fairly late in the progression of obesity and probably are not initiating events of inflammation and development of sustained insulin resistance. Evidence has accumulated showing that other changes in adipose-resident immune cells may precede these events. Under this scenario, ATMs will be effectors of a coordinated inflammatory response that includes the accumulation of proinflammatory T cells (CD8+ and Th1 CD4+ T cells) and the loss of anti-inflammatory regulatory T cells (Tregs), as well as the appearance of B cells, NK cells, NKT cells, eosinophils, neutrophils, and mast cells [
Adipocytes in lean adipose tissue produce factors such as IL-4 and IL-13 that induce M2 activation of macrophages and Th2 activation of CD4+ T cells and maintain Treg cell and eosinophil numbers. In obesity, the progressive accumulation of adipose tissue is accompanied by early increased infiltration of proinflammatory CD8+ T cells and a shift towards a higher CD8+/CD4+ ratio. CD8+ infiltration appears to be a key event preceding the depletion of adipose Tregs and the increased CD4+ Th1 cell activation observed in murine models of diet-induced obesity [
Neutrophils are known to play a role in the early stages of inflammatory responses, and it has been recently reported a sustained increased in adipose tissue neutrophil content in HFD-induced obesity with neutrophil secreted elastase being a key effector in this process [
In the 1980s, a new cell population known as “natural suppressor cells,” distinct from T and NK cells, was described in the bone marrow and spleen of tumor-bearing mice [
In mice, MDSC are commonly identified as coexpressing the cell surface markers CD11b and Gr-1. Since there are several subpopulations within Gr-1+CD11b+ cells, several groups further subcategorized MDSC into “monocytic” MDSC (CD11b+Ly6G-
In the steady state, MDSCs are predominantly present in the bone marrow and participate in the normal process of myelopoiesis. However, under various pathological inflammatory conditions such as cancer, infection, sepsis, graft-versus-host disease, and bone marrow transplantation, a variety of cytokines and soluble factors released induce rapid expansion of MDSC that will accumulate in peripheral lymphoid organs and blood, as well as in tumors, where they have been described to block CD4+ and CD8+ T-cell responses thus favoring cancer development [
Recently, an exciting observation has been described by Xia et al., showing that MDSCs and M2 macrophage induction may be a physiological response to promotion of insulin sensitivity [
The complex alterations in adipose tissue secretion of cytokines, adipokines, and chemokines and immune cell composition observed in adipose tissue-related pathologies such as obesity (Figure
Adipose tissue-resident cells, cytokines, and hormones: role in insulin sensitivity (adapted and updated from [
The authors do not report any conflict of interests.
This work was supported by the Centre National de la Recherche Scientifique (CNRS). The authors thank Dr. G. Rocheleau for his careful reading of the paper. Kassem Makki was funded by a PhD fellowship from Lille II University.