Adipose Tissue Inflammation in the Pathogenesis of Type 2 Diabetes ...

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Sep 15, 2015 - Obesity is associated with inflammation in adipose tissue, namely an infiltration and expansion of macrophages, which produce inflammatory ...
Curr Diab Rep (2015) 15: 92 DOI 10.1007/s11892-015-0670-x

PATHOGENESIS OF TYPE 2 DIABETES AND INSULIN RESISTANCE (RM WATANABE, SECTION EDITOR)

Adipose Tissue Inflammation in the Pathogenesis of Type 2 Diabetes Ayano Kohlgruber 1 & Lydia Lynch 1,2

Published online: 15 September 2015 # Springer Science+Business Media New York 2015

Abstract At least 2.8 million people die each year as a result of being overweight or obese, and the biggest burden being obesity-related diseases. Overweight and obesity account for a major proportion of type 2 diabetes (T2D) cases. Obesity is associated with inflammation in adipose tissue, namely an infiltration and expansion of macrophages, which produce inflammatory cytokines that interfere with insulin signaling, and a loss of protective cells that promote adipose homeostasis. Thus, it is now clear that inflammation is an underlying cause or contributor to T2D as well as many other obesityinduced diseases, including atherosclerosis and cancer. Inflammatory pathways contribute to impaired glucose handling by adipocytes, hepatocytes, and muscle cells and interfere with insulin production and insulin signaling. This review highlights the roles of the different immune populations in lean adipose tissue and their importance in tissue homeostasis to keep inflammation at bay. We also discuss the changes that occur in these immune cells during the development of obesity, which has detrimental effects on the health of adipose tissue, and local and systemic insulin resistance.

This article is part of the Topical Collection on Pathogenesis of Type 2 Diabetes and Insulin Resistance * Lydia Lynch [email protected] Ayano Kohlgruber [email protected] 1

Division of Rheumatology, Immunology and Allergy, Department of Medicine Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

2

Division of Endocrinology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

Keywords Immune system . Obesity . Type 2 diabetes . Innate immunity . Adipose tissue . Inflammation

Introduction Adipose tissue has a substantial and unique immune system, which was largely under-appreciated until recently. While the primary role of adipose tissue is not immunological, the resident specialized immune system here is important for tissue homeostasis. In the lean state, the adipose immune system is polarized in an anti-inflammatory regulatory state which is likely critical to keeping inflammation at bay in this dynamic organ which is constantly remodeling in response to nutrient intake and energy expenditure. However, excessive amounts of visceral adipose tissue predisposes to a myriad of diseases. Over-nutrition and obesity also cause inflammation in adipose tissue, which is now recognized as an underlying cause or contributor to many obesity-related diseases including insulin resistance and T2D, atherosclerosis, and cancer. Recognition that the immune system can regulate metabolic pathways has prompted a new way of thinking about diabetes and weight management. Immune aggregates in adipose tissue, called Bmilky spots,^ were first identified in 1874 [1]. In humans, the visceral omentum adipose depot has been termed Bthe policeman of the abdomen^ by surgeons who have long used the healing properties of the omentum to protect and seal sites of injury and infection [2]. Recently, some light was shed on the innate response of adipose tissue in a study showing that dermal adipocytes participate in the defense against bacterial infection in skin by producing cathelicidins [3]. A similar mechanism may be true for abdominal infections, where the human omentum plays a protective role in sealing the site from the rest of the abdomen. In addition to the innate immune functions of

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adipocytes, there is cross-talk between resident immune cells and adipocytes. This is likely to have been beneficial through evolution for both systems to coordinate energy stores available for survival through times of starvation and pathogen challenge. However, the major challenge of the twenty-first century is excess food intake and adiposity. Obesity has major effects on the systemic and resident adipose immune system, and this, in turn, accelerates obesity and metabolic disease in a vicious cycle. The inflammatory effects of obesity were first described in 1993, which it was reported that obese adipose tissue expressed elevated TNF-α levels [4]. This study also linked inflammation with insulin resistance, showing that TNF-α interferes with insulin signaling [4], and they subsequently showed that mice lacking TNF-α are protected from obesity-induced insulin resistance [5]. These studies, and others, introduced the field of immunometabolism, and since then, many immune-related molecules and cells have been implicated in the pathogenesis of obesity and diabetes. It was initially thought that adipocytes were the source of TNF-α, but now, it is more widely accepted that resident and infiltrating macrophages are the major source of TNF-α and other inflammatory cytokines in obesity. A picture has emerged in which a battle ensues between inflammatory M1 macrophages and regulatory cells, including invariant natural killer T (iNKT) cells and T regulatory (Treg) cells which can reverse inflammation and correct the metabolic disorder [6]. The net result is chronic sterile inflammation, which is a feature of most of the conditions that obesity causes. Thus, the involvement of the immune system in metabolism and weight control represents an entirely new therapeutic direction for treating obesity and T2D. The purpose of this review is, first, to highlight the features and functions of immune cells that are present in the adipose tissue at steady state and serve as gatekeepers of healthy adipose tissue and, second, to discuss what happens during adipose tissue inflammation that disrupts natural homeostasis and triggers the transition to a chronically inflamed organ. Lastly, we will discuss current therapeutic strategies that specifically target immune modulation as a way to ameliorate obesity and obesity-driven T2D.

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body. A major component of the adipose immune system is non-MHC-restricted unconventional T cells which are often less diverse in terms of antigen recognition, including iNKT cells, γδ T cells, and mucosal-associated invariant T (MAIT) cells. In addition, at steady state, the adipose tissue is predominantly characterized by immune cells that promote a regulatory anti-inflammatory immune state. Alternatively activated macrophages (AAMs) [7], iNKT cells [8], Treg cells [9, 10], eosinophils, and group 2 innate lymphoid cells (ILC2s) [11, 12] are present at high proportions in adipose tissue. They produce cytokines and factors that have been shown to modulate adipocyte function. These cells appear to be crucial to maintaining a non-inflammatory environment in a dynamic tissue that changes daily in response to feeding and fasting [13]. However, obesity triggers major changes in the adipose immune system, as early as 2–3 days after switching to a highfat diet (HFD) in mice. The first effects are an infiltration of neutrophils [14], and accumulation of macrophages, through infiltration and local proliferation [7, 15, 16], and a subsequent loss of protective lymphocytes [17, 18]. How this inflammation is triggered is not completely understood, but possible mechanisms include hypoxia [19], or lipotoxicity triggered by hypertrophic adipocytes [20, 21], endoplasmic reticulum, or potentially TLR activation through free fatty acid sensing [22]. It is likely that a combination of all of these may trigger signals to the immune system such as increased chemokine production by adipocytes or adipose leukocyte cells that induce immune infiltration. There may also be antigens in adipose tissue which are increased or decreased as well as costimulatory signals that activate resident leukocytes to produce cytokines and chemokines. All subsets of resident immune cells in adipose tissue have been shown to play a role in either the development of or protection from inflammation that drives obesity-induced metabolic disease [13, 23] (Fig. 1). This suggests that the adipose immune system is tightly controlled and highly interactive, with any aberrations affecting metabolism, energy storage, insulin sensitivity, and glycemic control. Here, we will review the recent literature on the immune populations in adipose tissue and how they protect from, or contribute to, insulin resistance and T2D.

Adipose Tissue Homeostasis in Lean and Obese States

Adipose Tissue Macrophages

Adipose tissue covers much of the human body and can account for 50 % of body mass in obesity. In mice, there are ~12 distinct adipose sites, each with a substantial immune system with collectively more lymphocytes than the liver. In humans, similar distinct adipose depots also exist, including omental, subcutaneous, mesenteric, pericolic, and brown adipose tissue as well as visceral adipose tissue surrounding the organs. Surprisingly, adipose lymphocytes have unique subsets and functions compared to their counterparts elsewhere in the

Adipose tissue macrophages are mostly polarized towards an M2 alternative phenotype in lean fat and play a critical role in remodeling and regulating metabolic homeostasis in adipose tissue [24]. M2 macrophages are interleukin (IL)-4 and IL-13 dependent and produce arginase and IL-10 [7]. Like adipocytes, adipose macrophages express peroxisome proliferatoractivated receptor gamma (PPARγ), which is important for the development of their M2 alternative activation, a phenotype crucial for metabolic health. Co-culture of PPARγ-

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Fig. 1 The ups and downs of the adipose immune system in lean and obese states

deficient macrophages with adipocytes led to reduced insulindependent glucose uptake in adipocytes, suggesting that M2 macrophages are directly involved in adipocyte metabolism [25]. However, in obesity, macrophages accumulate by infiltration and proliferation, and the balance shifts from M2 to an M1 classically activated pro-inflammatory phenotype. M1 macrophages express CD11c and produce TNF-α, IL-6, and

ROS [7, 15]. M2 macrophages are the dominant-type resident in adipose tissue at steady state in lean animals, whereas proinflammatory M1 macrophages accumulate in obesity. It is well documented that the accumulation of M1 macrophages plays a role in the development of insulin resistance. However, there is strong evidence that the initial infiltration of macrophages at the onset of obesity is a protective

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mechanism to buffer the tissue and cells from lipotoxicity by engulfing free fatty acids from rupturing adipocytes. In agreement with this hypothesis, deleting PPARγ specifically on macrophages causes increased fat mass, insulin resistance, and diabetes [25]. Furthermore, eliminating macrophages and monocytes by injecting clodronate liposomes during the onset of obesity prevents macrophage infiltration but not inflammation during these early stages of obesity [26]. However, macrophage depletion has also been shown to be protective during the later stages of obesity [27]. In addition, macrophages infiltrate adipose tissue during fasting in mice [28], supporting the hypothesis that macrophage infiltration is a physiological response to protect from lipotoxicity, which occurs when lipolysis is induced in the fasting state. The protective role that macrophages play in lean mice and in buffering in the initial stages of a high-fat diet is lost as obesity progresses. M1 macrophages outnumber M2, and inflammatory program is induced including production of inflammatory cytokines including TNF-α and IL-6, and this is also true in human obesity also [29]. The cJun NH(2)-terminal kinase (JNK) signaling pathway is activated in macrophages in obesity and contributes to insulin resistance, and deletion of JNK specifically inside adipose macrophages is sufficient to protect mice from metabolic disease [30]. Thus, although adipose tissue macrophages are likely essential for metabolic health, in obesity, it is well documented that they are major contributors to insulin resistance and T2D in humans and in mice, and therapeutic strategies that aim to prevent their infiltration or activation are currently in progress.

iNKT Cells iNKT cells represent the innate lipid-sensing arm of the immune system [31, 32], meaning that unlike adaptive T cells that recognize peptide through MHC molecules, iNKT cells recognize lipid antigens presented by CD1d [32]. We have shown that iNKT cells are enriched in human and murine adipose tissue [17, 18]. Furthermore, using congenic parabiotic mice, we have shown that adipose iNKT cells are a tissue resident with little influx from the circulation and are a unique anti-inflammatory regulatory population [33]. However, adipose iNKT cells are severely reduced in obesity [17, 18, 34]. iNKT cells are potent transactivators of other immune cells and can act as a bridge between innate and adaptive immunity; thus, their loss in obesity represents the loss of a major regulatory population in adipose tissue. This hypothesis is still under debate as studies using mice lacking iNKT cells (CD1d−/− or Jα18−/− mice) have found varying results. The majority of studies have found that iNKT cell-deficient mice have worse metabolic disorder and are more obese [18, 34–36], but other studies have found an absence or negative impact of iNKT cells on diabetes and obesity in mice [37, 38].

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Other factors may explain these differences, such as different diets and experimental procedures. Moreover, recent work highlighting the microbiome and its effects on weight gain and energy expenditure demonstrates that the particular microbial composition can significantly impact circulating endotoxin levels and influence severity of adipose tissue inflammation, adipocyte hyperplasia, and insulin resistance [39]. Institutional differences between bacterial flora will thus confound results between labs. Fortunately, another way to study the effects of iNKT cells on metabolic control where the impact of the microbiome is lessened is to activate iNKT cells with their potent lipid ligand, α-galactosylceramide (αGalCer). We, and others, have found that injection of αGalCer in obesity expands the diminished iNKT cell pool and causes rapid weight loss, anti-inflammatory macrophage polarization, and reversal of glucose and insulin sensitivity without hypoglycemia [18, 33–35, 40]. Although the differences in iNKT cell-deficient mice have not been fully resolved, the majority of findings suggest that adipose resident iNKT cells play a critical role in keeping local inflammation at bay and protecting against metabolic disorder in obesity.

MAIT Cells Mucosal-associated invariant T (MAIT) cells and iNKT cells are evolutionary conserved T cell subsets. Like iNKT cells, MAIT cells express an invariant T cell receptor chain (Vα7.2Jα33 chain in humans), likely meaning that they recognize a limited antigen repertoire. Recently, it was discovered that MAIT cells recognize vitamin metabolites including vitamin B2 (riboflavin) metabolites produced by bacteria and derivatives of folic acid, which are presented to MAIT cells in MR1 molecules [41•, 42]. MAIT cells are more numerous in the blood than in iNKT cells and are also found in the intestinal mucosa, liver, and lung. Recently, it was reported that MAIT cells are enriched in human adipose tissue [43, 44]. Furthermore, MAIT cells’ numbers and functions are altered in obese and T2D patients. In adipose tissue, MAIT cells appear to play a regulatory role, producing IL-10, but are reduced in number in obese individuals, which correlated with worsening glycemic control [43]. MAIT cells were also decreased in the circulation in patients with T2D, even in the absence of obesity, and were further reduced in obese T2D patients [44]. Furthermore, circulating MAIT cells were more activated and skewed towards an inflammatory cytokine profile in obesity, which may contribute to the pathogenesis of metabolic disease [43, 44]. Although the role of MAIT cells in T2D is not yet fully understood, MAIT cells may interfere with insulin signaling through their IL-17 production. The IL-17R is expressed on adipocytes, and IL-17 can impair their adipogenesis and glucose uptake and insulin sensitivity,

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although it was associated with reduced fat mass accumulation [45].

Group 2 Innate Lymphoid Cells Innate lymphoid cells (ILCs) are key regulators of the immune system, and they have recently been linked to the regulation of host metabolism. In 2010, innate lymphocytes that formed fatassociated lymphoid clusters and produced Th2 cytokines were reported in various adipose depots, particularly mesenteric adipose [11]. The Locksley and Chawla labs later found that ILC2 (Th2-like ILCs) cells sustained eosinophil and alternatively activated a number of macrophages to promote glucose homeostasis [12]. Furthermore, activating adipose ILC2s promotes beige adipocyte differentiation and thermogenesis and beneficially induces weight loss [46]. In the human adipose tissue, ILC2 could also induce beiging of white adipose tissue when activated with IL-33, independent of eosinophils. Human adipose ILC2s produce methionineenkephalin peptides that can directly act on adipocytes to upregulate the thermogenic browning program [47••]. These pathways also involved glycemic control, as mice lacking IL-33, which activates ILC2s, exhibited fasting euglycemic hyperinsulinemia, increased HOMA-IR values, and impaired glucose and insulin tolerance. Treatment of obese mice with rIL-33 resulted in increased adipose ILC2s, less fat mass, and improved glucose homeostasis [47••]. This study also suggests that some of the findings from murine thermogenesis induction might be translatable to humans and that inducing thermogenesis in humans through immune cell activation may be a potential target for weight loss and glycemic control.

T Regulatory Cells T regulatory (Treg) cells are adaptive αβT cells that play an important role in maintaining immunologic self-tolerance, and provide protection from autoimmune pathology [48]. They are enriched in visceral adipose tissue comprising up to 60 % of the CD4+ T cell population and accumulated with age in contrast to their splenic, lymph node, lung, and liver counterparts [10]. They also exhibit clonal expansion in response to a yet unidentified antigen(s) in the adipose tissue [49]. Like all Treg cells, adipose Treg cells express forkhead-winged-helix transcription factor (Foxp3), the master regulator for their development and function. In contrast to other Treg cells, adipose Treg cells depend on interferon regulatory factor 4 (Irf4), basic leucine zipper transcription factor ATF-like (Batf) [50•], and peroxisome proliferator-activated receptor-c (PPARγ) [51], for their accumulation, phenotype, and function. Consequently, they have enhanced expression of IL-10 and ILrl1 transcripts that define their role as anti-inflammatory

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cells in adipose tissue [10, 50•]. In support, IL-10 has been well characterized as an anti-inflammatory cytokine by limiting monocyte chemoattractant protein (MCP)-1 production by adipocytes and also can act as an insulin sensitizer by inhibiting the downregulation of Glut4 on adipocytes in response to TNF-α signaling [10]. Moreover, recent work has highlighted the importance of IL-33 signaling through the IL33 receptor, ST2, for the identity and protective functions of adipose Treg cells at steady state. Short-term injection of recombinant IL-33 expands the local Treg population [12, 49] and markedly improves glycemic indices in obese mice, suggesting a potential therapeutic strategy to protect adipose tissue inflammation. Thus, adipose Treg cells represent an important anti-inflammatory population in adipose tissue, which, like iNKT cells, are reduced in number in obesity, contributing to inflammation-induced insulin resistance.

B Cells In addition to the myriad of T lymphocytes and their effects on adipose tissue homeostasis, recent work has unveiled important physiological roles of B cells in the adipose tissue. B1a cells develop in the fetal liver and are the primary producers of natural IgM antibodies found in the serum [52]. Surprisingly, these cells are a prominent source of IL-10 in the adipose tissue and help mediate glucose tolerance [53]. Moreover, secreted IgM produced by B1a cells suppresses the ability of adipose tissue macrophages to produce TNF-α, IL-6, and MCP-1 and is also thought to promote apoptotic debris clearance. Indeed, injecting sorted IL-10-deficient B1a cells or purified polyclonal IgM into obese mice strongly protects from diet-induced insulin resistance [53], bolstering their role as anti-inflammatory guardians of adipose tissue. In addition, Nishimura et al., have characterized a population of B regulatory (Breg) cells enriched in the subcutaneous and visceral adipose tissue that lack CD5 expression and produce IL-10 to protect mice from insulin resistance [54]. Unlike other mature B cells that produce IL-10, these Breg cells are phenotypically distinct, expressing CXCR4+IL-10Ra+, and constitutively produce IL-10 without the need for LPS stimulation [54]. Whether the IL-10 produced by the B1a and Breg cells is overlapping and redundant or whether each cell type exerts additional unique functions to maintain adipose tissue homeostasis warrants further investigation. However, during obesity, the anti-inflammatory protection mediated by B1a cells may be overshadowed by infiltrating B2 cells that skew the adipose tissue towards an inflammatory environment [53]. During obesity, B2 cells stimulate IFN-γ+, CD4+, and CD8+ T cell responses through MHC I and MHC II antigen presentation, respectively [55], and increase local concentrations of inflammatory IgG1 antibodies as a consequence of this T-B cell feedback loop. Specifically, antibody class switching activates

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adipose tissue macrophages through engagement of the Fc receptor to induce oxidative burst and pro-inflammatory cytokine production [55]. In agreement, BAFF-deficient mice that lack B2 cells but are B1a cell replete have improved glucose tolerance after 9 weeks on a HFD compared to WT, and adoptive transfer of B1a cells and B2 cells into B cell-deficient mice improves and worsens glycemic control, respectively [53]. Lastly, administration of anti-CD20 treatment that specifically depletes B2 cells, and not B1a cells, ameliorates insulin resistance. Likewise, serum transfer of purified IgG from obese mice exacerbates insulin resistance and adipose tissue inflammation. These studies thus support the dichotomous roles of B1a and Breg cells as anti-inflammatory guardians and B2 cells as pro-inflammatory inciters of adipose tissue.

Eosinophils Eosinophils are granulocytes that develop in the bone marrow and depend on the cytokine interleukin-5 (IL-5) and the transcription factor GATA-binding protein 1 (GATA-1) for their maturity [56, 57]. Inflammatory cues activate eosinophils and signal their recruitment to tissue sites in response to eotaxin chemokines [58]. Traditionally, they have been associated with immune responses to helminth infections and asthma, but eosinophils have more recently emerged as a surprising key effector population in the adipose tissue to control systemic metabolism. At steady state, eosinophils account for 4– 5 % of the adipose stromal vascular fraction (SVF) and receive IL-5 signals from adipose tissue ILC2s to maintain their function and frequency [12]. They are a key source of local IL-4 driving alternatively activated macrophages to secrete antiinflammatory cytokines like IL-10 and thermogenic catecholamines to promote beiging of adipocytes in situ [9, 59]. As expected, mice strains deficient in eosinophils (ΔdblGATA mice or Red5 mice) gain more weight, exhibit larger visceral adiposity, and have worsened glucose and insulin tolerance compared to wild-type (WT) controls Conversely, IL-5overexpressing transgenic mice or mice receiving helminth challenges have bolstered eosinophil responses, increased arginase-1-positive macrophages, and are protected from obesity and insulin resistance [9, 12]. Moreover, chronic cold exposure and physical exercise stimulate adipocytes and myocytes, respectively, to release meteorin-like (metrnl) hormone and recruit eosinophils to the adipose tissue, thus increasing expression of the thermogenic and antiinflammatory gene programs in fat [60]. Unfortunately, increasing weight correlates with decreasing eosinophil numbers in obese mice and strategies to boost eosinophil frequencies using recombinant IL-5 (direct) or IL-33 (indirect through ILC2s) treatment protect mice from worsening glucose tolerance and insulin resistance [12, 61]. Eosinophils are an important guardian in the adipose tissue, and strategies to support

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their endogenous function provide an attractive strategy in dampening adipose tissue inflammation during obesity and T2D.

CD8+ T Cells At steady state, CD8+ T lymphocytes comprise a small percentage (3–5 % in mice) of the total SVF in adipose tissue. During obesity, however, they increase in number (10 % in mice) and increasing CD8a expression strongly correlates with increasing BMI (humans) [62, 63]. In mice deficient in CD8 T cells, administration of neutralizing monoclonal antibodies (mAb) to deplete CD8 T cells during HFD feeding results in improved glycemic indices, reduction in TNF-α and IL-6 levels, and protection from M1 macrophage infiltration without changes in body weight or adiposity [62]. Once in the adipose tissue, it is thought that CD8 T cells produce increased concentrations of chemotactic proteins such as MCP-1, MCP-3, and RANTES, and transwell studies validate the ability of CD8 T cells to recruit monocytes and macrophages [62]. It is also suggested that adipose CD8 T cells from obese mice produce more TNF-α and IFN-γ, activating macrophages, as seen by upregulation of cell surface MHC II expression [62]. Finally, treatment of obese mice with depleting CD8 T cell mAb for 2 weeks improves glucose and insulin handling, thus suggesting that CD8 T cells are an important component for the initiation and maintenance of adipose tissue inflammation [62]. Whether a specific peptide antigen presented on MHC I molecules promotes CD8+ T cell activation and proliferation in the adipose tissue remains an intriguing, but unanswered, question.

CD4+ T Cells CD4+ T cells have the ability to differentiate into various subsets upon receiving external cytokine cues during activation and are aptly phenotyped based on the transcription factors and cytokines they express (Th1, Th2, Th17, etc.) [64]. A role for MHC class II-restricted CD4+ T cells during lean and obese states has not been clearly outlined. Various reports have pointed to an accumulation of Th1 [65] and Th17 [66, 67] cells in the adipose tissue of obese mice and humans, where increasing BMI correlates with decreasing Treg cells [68]. IFN-γ produced by Th1 cells enhances proinflammatory macrophage release of IL-1β, IL-6, and TNF-α [69] to promote insulin resistance, while IL-22 produced by Th17 cells induces pro-IL-1β transcription through the activation of C-Jun pathways, thereby amplifying the inflammatory response in macrophages [70]. More recently, retinol binding protein (RBP), a transporter that has been associated with an increased risk for developing insulin resistance,

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was identified to upregulate surface expression of MHC II on alternatively activated macrophages through JNK signaling and potentiate Th1 differentiation [71]. Indeed, macrophagespecific MHC II knockout mice (LysM-Cre×MHC II fl/fl) are protected from obesity insulin resistance and prevent the generation of effector/memory CD4 T cells [65]. Interestingly, evidence exists for clonal CD4 T cell expansion in the adipose tissue, but a major unanswered question still remains the nature of the peptide being presented by APCs on MHC II molecules to elicit adipose tissue inflammation (or protection) during obesity.

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