Immunological Goings-on in Visceral Adipose Tissue
2013; Cell Press; Volume: 17; Issue: 6 Linguagem: Inglês
10.1016/j.cmet.2013.05.008
ISSN1932-7420
Autores Tópico(s)IL-33, ST2, and ILC Pathways
ResumoChronic, low-grade inflammation of visceral adipose tissue, and systemically, is a critical link between recent strikingly parallel rises in the incidence of obesity and type 2 diabetes. Macrophages have been recognized for some time to be critical participants in obesity-induced inflammation of adipose tissue. Of late, a score of other cell types of the innate and adaptive arms of the immune system have been suggested to play a positive or negative role in adipose tissue infiltrates. This piece reviews the existing data on these new participants; discusses experimental uncertainties, inconsistencies, and complexities; and puts forward a minimalist synthetic scheme. Chronic, low-grade inflammation of visceral adipose tissue, and systemically, is a critical link between recent strikingly parallel rises in the incidence of obesity and type 2 diabetes. Macrophages have been recognized for some time to be critical participants in obesity-induced inflammation of adipose tissue. Of late, a score of other cell types of the innate and adaptive arms of the immune system have been suggested to play a positive or negative role in adipose tissue infiltrates. This piece reviews the existing data on these new participants; discusses experimental uncertainties, inconsistencies, and complexities; and puts forward a minimalist synthetic scheme. Classic studies, now decades old, revealed that visceral adipose tissue (VAT) is a site where cells and molecules that control metabolism and immunity interplay, with important consequences for organismal homeostasis. Twenty years ago, Hotamisligil et al. demonstrated that tumor necrosis factor α (TNF-α) messenger RNA (mRNA) and protein were induced in the epididymal fat pad of obese rodents and that neutralization of this cytokine improved their characteristic systemic insulin resistance (Hotamisligil et al., 1993Hotamisligil G.S. Shargill N.S. Spiegelman B.M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.Science. 1993; 259: 87-91Crossref PubMed Scopus (6138) Google Scholar). Ten years later, two groups independently reported an impressive accumulation of macrophage-associated gene transcripts and of cells expressing the F4/80 or CD68 marker, presumed to be macrophages, with increasing adiposity in mice and humans (Xu et al., 2003Xu H. Barnes G.T. Yang Q. Tan G. Yang D. Chou C.J. Sole J. Nichols A. Ross J.S. Tartaglia L.A. Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.J. Clin. Invest. 2003; 112: 1821-1830Crossref PubMed Scopus (5186) Google Scholar; Weisberg et al., 2003Weisberg S.P. McCann D. Desai M. Rosenbaum M. Leibel R.L. Ferrante Jr., A.W. Obesity is associated with macrophage accumulation in adipose tissue.J. Clin. Invest. 2003; 112: 1796-1808Crossref PubMed Scopus (7458) Google Scholar). These studies catalyzed the emerging notion that chronic, low-grade inflammation is a critical link between obesity and a spectrum of metabolic abnormalities, including insulin resistance, type 2 diabetes, and fatty-liver disease. Other proinflammatory cytokines, notably interleukin-6 (IL-6) and IL-1β, were eventually implicated (Pradhan et al., 2001Pradhan A.D. Manson J.E. Rifai N. Buring J.E. Ridker P.M. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus.JAMA. 2001; 286: 327-334Crossref PubMed Scopus (3388) Google Scholar; Wen et al., 2011Wen H. Gris D. Lei Y. Jha S. Zhang L. Huang M.T. Brickey W.J. Ting J.P. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling.Nat. Immunol. 2011; 12: 408-415Crossref PubMed Scopus (1282) Google Scholar). And the increase in macrophage representation was soon found to be accompanied by an altered localization within the adipose tissue and population evolution to a more proinflammatory phenotype (Lumeng et al., 2007aLumeng C.N. Bodzin J.L. Saltiel A.R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization.J. Clin. Invest. 2007; 117: 175-184Crossref PubMed Scopus (3339) Google Scholar, Lumeng et al., 2007bLumeng C.N. Deyoung S.M. Bodzin J.L. Saltiel A.R. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity.Diabetes. 2007; 56: 16-23Crossref PubMed Scopus (770) Google Scholar; Nguyen et al., 2007Nguyen M.T. Favelyukis S. Nguyen A.K. Reichart D. Scott P.A. Jenn A. Liu-Bryan R. Glass C.K. Neels J.G. Olefsky J.M. A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways.J. Biol. Chem. 2007; 282: 35279-35292Crossref PubMed Scopus (776) Google Scholar). More importantly, the functional relevance of macrophages and their phenotypic changes was established through loss- and gain-of-function experiments (e.g., Patsouris et al., 2008Patsouris D. Li P.P. Thapar D. Chapman J. Olefsky J.M. Neels J.G. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals.Cell Metab. 2008; 8: 301-309Abstract Full Text Full Text PDF PubMed Scopus (610) Google Scholar; Weisberg et al., 2006Weisberg S.P. Hunter D. Huber R. Lemieux J. Slaymaker S. Vaddi K. Charo I. Leibel R.L. Ferrante Jr., A.W. CCR2 modulates inflammatory and metabolic effects of high-fat feeding.J. Clin. Invest. 2006; 116: 115-124Crossref PubMed Scopus (1253) Google Scholar; Kanda et al., 2006Kanda H. Tateya S. Tamori Y. Kotani K. Hiasa K. Kitazawa R. Kitazawa S. Miyachi H. Maeda S. Egashira K. Kasuga M. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity.J. Clin. Invest. 2006; 116: 1494-1505Crossref PubMed Scopus (1972) Google Scholar; Kamei et al., 2006Kamei N. Tobe K. Suzuki R. Ohsugi M. Watanabe T. Kubota N. Ohtsuka-Kowatari N. Kumagai K. Sakamoto K. Kobayashi M. et al.Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance.J. Biol. Chem. 2006; 281: 26602-26614Crossref PubMed Scopus (682) Google Scholar). A “macrophago-centric” view of obesity-associated inflammation reigned for many years, and was recently reviewed (Osborn and Olefsky, 2012Osborn O. Olefsky J.M. The cellular and signaling networks linking the immune system and metabolism in disease.Nat. Med. 2012; 18: 363-374Crossref PubMed Scopus (1131) Google Scholar; Chawla et al., 2011Chawla A. Nguyen K.D. Goh Y.P. Macrophage-mediated inflammation in metabolic disease.Nat. Rev. Immunol. 2011; 11: 738-749Crossref PubMed Scopus (960) Google Scholar). Of late, there has been growing interest in the roles of additional members of both the innate and adaptive arms of the immune system in regulating organismal metabolism. Besides macrophages, several other immune cell types have been implicated: mast cells, neutrophils, eosinophils, type 2 innate lymphoid cells (ILCs), CD8+ and CD4+ T cells, B cells, Foxp3+ regulatory T (Treg) cells, CD4−8− γδ T cells, and natural killer T cells (NKT cells). What sense are we to make of this intimidatingly complex cast of characters? This piece will lay out the existing body of data on the participants in obesity-associated inflammation; address sources of uncertainty, inconsistency, and complexity; and suggest a minimalist synthetic scheme. Immune system cells, above all macrophages, accumulate in the VAT (in particular, in the epididymal depot) of both lean and obese individuals. In the lean state, most macrophages have an anti-inflammatory phenotype, often referred to as “M2 like” or “alternatively activated” (Chawla et al., 2011Chawla A. Nguyen K.D. Goh Y.P. Macrophage-mediated inflammation in metabolic disease.Nat. Rev. Immunol. 2011; 11: 738-749Crossref PubMed Scopus (960) Google Scholar; Osborn and Olefsky, 2012Osborn O. Olefsky J.M. The cellular and signaling networks linking the immune system and metabolism in disease.Nat. Med. 2012; 18: 363-374Crossref PubMed Scopus (1131) Google Scholar; Lumeng et al., 2007aLumeng C.N. Bodzin J.L. Saltiel A.R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization.J. Clin. Invest. 2007; 117: 175-184Crossref PubMed Scopus (3339) Google Scholar, Lumeng et al., 2007bLumeng C.N. Deyoung S.M. Bodzin J.L. Saltiel A.R. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity.Diabetes. 2007; 56: 16-23Crossref PubMed Scopus (770) Google Scholar; Nguyen et al., 2007Nguyen M.T. Favelyukis S. Nguyen A.K. Reichart D. Scott P.A. Jenn A. Liu-Bryan R. Glass C.K. Neels J.G. Olefsky J.M. A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways.J. Biol. Chem. 2007; 282: 35279-35292Crossref PubMed Scopus (776) Google Scholar). Their differentiation and/or survival depends on IL-4 and IL-13; they express the cell-surface markers CD11b, F4/80, CD301, and CD206, and they secrete anti-inflammatory cytokines such as IL-10 and IL-1 receptor antagonist (IL-1Ra). This type of macrophage can expand somewhat in the obese state, but there is a much more striking accumulation of a proinflammatory subset, denoted “M1 like” or “classically activated” (Lumeng et al., 2007aLumeng C.N. Bodzin J.L. Saltiel A.R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization.J. Clin. Invest. 2007; 117: 175-184Crossref PubMed Scopus (3339) Google Scholar, Lumeng et al., 2007bLumeng C.N. Deyoung S.M. Bodzin J.L. Saltiel A.R. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity.Diabetes. 2007; 56: 16-23Crossref PubMed Scopus (770) Google Scholar; Nguyen et al., 2007Nguyen M.T. Favelyukis S. Nguyen A.K. Reichart D. Scott P.A. Jenn A. Liu-Bryan R. Glass C.K. Neels J.G. Olefsky J.M. A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways.J. Biol. Chem. 2007; 282: 35279-35292Crossref PubMed Scopus (776) Google Scholar). These cells, whose differentiation is promoted by agents such as lipopolysaccharide and interferon γ (IFN-γ), display the marker CD11c in addition to F4/80 and CD11b and produce proinflammatory mediators like TNF-α, IL-6, IL-1β, nitric oxide (NO), IL-12, etc. The M1/M2-like dichotomy is certainly an oversimplification in this context, as macrophages with intermediate properties (Shaul et al., 2010Shaul M.E. Bennett G. Strissel K.J. Greenberg A.S. Obin M.S. Dynamic, M2-like remodeling phenotypes of CD11c+ adipose tissue macrophages during high-fat diet—induced obesity in mice.Diabetes. 2010; 59: 1171-1181Crossref PubMed Scopus (278) Google Scholar; Herrero et al., 2010Herrero L. Shapiro H. Nayer A. Lee J. Shoelson S.E. Inflammation and adipose tissue macrophages in lipodystrophic mice.Proc. Natl. Acad. Sci. USA. 2010; 107: 240-245Crossref PubMed Scopus (118) Google Scholar) or with an extreme phenotype reminiscent of that of foam cells in atherosclerotic lesions (Xu et al., 2003Xu H. Barnes G.T. Yang Q. Tan G. Yang D. Chou C.J. Sole J. Nichols A. Ross J.S. Tartaglia L.A. Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.J. Clin. Invest. 2003; 112: 1821-1830Crossref PubMed Scopus (5186) Google Scholar; Prieur et al., 2011Prieur X. Mok C.Y. Velagapudi V.R. Núñez V. Fuentes L. Montaner D. Ishikawa K. Camacho A. Barbarroja N. O’Rahilly S. et al.Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice.Diabetes. 2011; 60: 797-809Crossref PubMed Scopus (252) Google Scholar) are also found in adipose tissue. As mentioned above, it is by now well established that anti-inflammatory macrophages promote local and systemic insulin sensitivity, while their proinflammatory counterparts induce insulin resistance, primarily via secreted mediators (Osborn and Olefsky, 2012Osborn O. Olefsky J.M. The cellular and signaling networks linking the immune system and metabolism in disease.Nat. Med. 2012; 18: 363-374Crossref PubMed Scopus (1131) Google Scholar; Chawla et al., 2011Chawla A. Nguyen K.D. Goh Y.P. Macrophage-mediated inflammation in metabolic disease.Nat. Rev. Immunol. 2011; 11: 738-749Crossref PubMed Scopus (960) Google Scholar). So we will not dwell on this aspect here. Additional innate immune cell types, whether of a pro- or anti-inflammatory nature, have more recently been implicated in obesity-induced metabolic aberrancies. Mast cells, once mature, reside in connective and mucosal tissue, where they are part of an “early-warning” system that infection or injury has occurred in the vicinity. They contain numerous granules loaded with preformed mediators, e.g., histamine, serotonin, heparin, serine proteases, eicosanoids, and cytokines (notably TNF-α and IL-1β). Upon mast cell activation, all or a select subset of these mediators are released in a rapid burst, activating the surrounding vasculature and promoting recruitment of additional inflammatory cell types. Liu et al. reported that there is a greater representation of mast cells in the adipose tissue of obese than lean mice and humans (Liu et al., 2009Liu J. Divoux A. Sun J. Zhang J. Clément K. Glickman J.N. Sukhova G.K. Wolters P.J. Du J. Gorgun C.Z. et al.Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice.Nat. Med. 2009; 15: 940-945Crossref PubMed Scopus (575) Google Scholar). Genetic mutations at the Kit locus, which lead to a mast cell deficiency, or pharmacological stabilization of mast cell granules resulted in less weight gain and VAT mass on a high-fat diet (HFD), reduction in VAT-resident macrophages and both adipose-tissue and circulating inflammatory mediators, and improvement in several indices of insulin sensitivity. IL-6 and IFN-γ, but not TNF-γ, were found to be important mediators of these effects. Neutrophils are also early participants in inflammatory reactions, recruited from the circulation by activated endothelium and/or by tissue-resident macrophages or mast cells. Upon appropriate stimulation, these short-lived cells release reactive oxygen species and nitrogen intermediates; degranulate, expelling serine proteases and other enzymes; and lay down extracellular traps, or NETs, constituted of extruded webs of chromatin and serine proteases. Besides being antimicrobial, these activities amplify inflammatory responses, through recruitment of circulating monocytes, for example. Neutrophils begin to accumulate in the VAT within days after mice are placed on a HFD, an increase that is sustained for at least 3 months on this diet (Talukdar et al., 2012Talukdar S. Oh Y. Bandyopadhyay G. Li D. Xu J. McNelis J. Lu M. Li P. Yan Q. Zhu Y. et al.Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase.Nat. Med. 2012; 18: 1407-1412Crossref PubMed Scopus (644) Google Scholar; Elgazar-Carmon et al., 2008Elgazar-Carmon V. Rudich A. Hadad N. Levy R. Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding.J. Lipid Res. 2008; 49: 1894-1903Crossref PubMed Scopus (336) Google Scholar). Genetic ablation of the gene encoding the critical neutrophil protease, elastase, or pharmacological inhibition of its activity substantially improved the inflammatory tone and metabolic indices of HFD-fed mice; conversely, injection of recombinant neutrophil elastase into mice on normal chow (NC) provoked glucose intolerance (Talukdar et al., 2012Talukdar S. Oh Y. Bandyopadhyay G. Li D. Xu J. McNelis J. Lu M. Li P. Yan Q. Zhu Y. et al.Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase.Nat. Med. 2012; 18: 1407-1412Crossref PubMed Scopus (644) Google Scholar). These alterations did not rely on body weight and VAT mass changes. Just as anti-inflammatory macrophages predominate in the benign infiltrates of VAT in lean mice, particular populations of anti-inflammatory innate immune cells have been found in these fat depots. Eosinophils circulate in the immature state and lodge in a limited range of tissues once mature, a range that is extended by parasite infection. Their differentiation and activation are critically dependent on IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF). They are granulocytes, releasing a broad array of pro- and anti-inflammatory mediators, in particular IL-4 and IL-13, known to be crucial for the differentiation and survival of anti-inflammatory, M2-like macrophages, including those residing in adipose tissue (Odegaard et al., 2007Odegaard J.I. Ricardo-Gonzalez R.R. Goforth M.H. Morel C.R. Subramanian V. Mukundan L. Red Eagle A. Vats D. Brombacher F. Ferrante A.W. Chawla A. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance.Nature. 2007; 447: 1116-1120Crossref PubMed Scopus (1599) Google Scholar; Kang et al., 2008Kang K. Reilly S.M. Karabacak V. Gangl M.R. Fitzgerald K. Hatano B. Lee C.H. Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity.Cell Metab. 2008; 7: 485-495Abstract Full Text Full Text PDF PubMed Scopus (547) Google Scholar). Wu et al.’s attention was drawn to eosinophils because they found them to be the major producers of IL-4 in VAT, and their representation in VAT to be inversely correlated with adiposity (Wu et al., 2011Wu D. Molofsky A.B. Liang H.E. Ricardo-Gonzalez R.R. Jouihan H.A. Bando J.K. Chawla A. Locksley R.M. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis.Science. 2011; 332: 243-247Crossref PubMed Scopus (965) Google Scholar). Mice impoverished in eosinophils (a Gata1−/− strain), and thereby anti-inflammatory macrophages, exhibited an increase in body and VAT weight, as well as more marked glucose intolerance and insulin resistance, when fed a HFD. Conversely, animals enriched in eosinophils (an IL-5 transgenic strain), and thus M2-like macrophages, showed a decline in these parameters. One step further removed is a recently discovered subset of innate lymphoid cells termed ILC2s. Like all ILCs, these cells are characterized by dependence on the transcription factor Id2 and the cytokine receptor common gamma chain (γc). They are widely distributed in mammalian tissues, and are reminiscent of T helper 2 (Th2) cells in their production of the cytokines IL-5 and IL-13. As IL-13 promotes differentiation of M2-like macrophages and IL-5 fosters the maturation and activities of eosinophils, which make most of the IL-4 required by M2 macrophages, Molofsky et al. were prompted to address their role in adipose tissue inflammation (Molofsky et al., 2013Molofsky A.B. Nussbaum J.C. Liang H.E. Van Dyken S.J. Cheng L.E. Mohapatra A. Chawla A. Locksley R.M. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages.J. Exp. Med. 2013; 210: 535-549Crossref PubMed Scopus (630) Google Scholar). Indeed, they found ILC2s to be the major source of both IL-5 and IL-13 in VAT and their representation in VAT to decline under a HFD regime. Genetically engineered or cytokine-promoted increases or decreases in ILC2s led to an enhancement or reduction, respectively, in VAT eosinophils and anti-inflammatory macrophages. These cellular changes were accompanied by the expected alterations in body weight, VAT weight, and measures of insulin resistance and glucose intolerance when the mice were put on a HFD. Together, these results implicate multiple members of the innate immune system in controlling adipose tissue inflammation and its downstream consequences—either positively (proinflammatory macrophages, mast cells, and neutrophils) or negatively (anti-inflammatory macrophages, eosinophils, and ILC2s). A concern that needs to be kept in mind when considering these findings is that in most cases—even for macrophages—optimum tools for precise manipulation of the cell type of interest are not currently available. Loss- or gain-of-function experiments often rely on manipulation of a factor thought to be required for differentiation or maintenance of the population (e.g., cKit for mast cells [Liu et al., 2009Liu J. Divoux A. Sun J. Zhang J. Clément K. Glickman J.N. Sukhova G.K. Wolters P.J. Du J. Gorgun C.Z. et al.Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice.Nat. Med. 2009; 15: 940-945Crossref PubMed Scopus (575) Google Scholar] or GATA1 or IL-5 for eosinophils [Wu et al., 2011Wu D. Molofsky A.B. Liang H.E. Ricardo-Gonzalez R.R. Jouihan H.A. Bando J.K. Chawla A. Locksley R.M. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis.Science. 2011; 332: 243-247Crossref PubMed Scopus (965) Google Scholar; Molofsky et al., 2013Molofsky A.B. Nussbaum J.C. Liang H.E. Van Dyken S.J. Cheng L.E. Mohapatra A. Chawla A. Locksley R.M. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages.J. Exp. Med. 2013; 210: 535-549Crossref PubMed Scopus (630) Google Scholar]) or an element thought to mediate one of the population’s critical effector mechanisms (e.g., degranulation for mast cells [Liu et al., 2009Liu J. Divoux A. Sun J. Zhang J. Clément K. Glickman J.N. Sukhova G.K. Wolters P.J. Du J. Gorgun C.Z. et al.Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice.Nat. Med. 2009; 15: 940-945Crossref PubMed Scopus (575) Google Scholar], elastase for neutrophils [Elgazar-Carmon et al., 2008Elgazar-Carmon V. Rudich A. Hadad N. Levy R. Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding.J. Lipid Res. 2008; 49: 1894-1903Crossref PubMed Scopus (336) Google Scholar], or IL-5 and IL-13 for ILCs [Molofsky et al., 2013Molofsky A.B. Nussbaum J.C. Liang H.E. Van Dyken S.J. Cheng L.E. Mohapatra A. Chawla A. Locksley R.M. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages.J. Exp. Med. 2013; 210: 535-549Crossref PubMed Scopus (630) Google Scholar]). But these manipulations are seldom exquisitely specific, and so many of them impact other cells or processes. Neither, in general, do they encompass the entire potential influence of the targeted cell type. So it is important to consider to what extent these imperfections might compromise the critical conclusions concerning obesity-associated inflammation. It is also important to be cognizant of the fact that the list of innate immune cell types contributing to obesity-associated inflammation might not be complete. A few classic cell types (e.g., basophils and NK cells) have not yet been adequately evaluated, and the quite new field of ILC biology is yielding more and more innate lymphocyte groupings with activities astonishingly parallel to those of adaptive lymphocyte subsets (Klose et al., 2013Klose C.S. Kiss E.A. Schwierzeck V. Ebert K. Hoyler T. d’Hargues Y. Göppert N. Croxford A.L. Waisman A. Tanriver Y. Diefenbach A. A T-bet gradient controls the fate and function of CCR6-RORγt+ innate lymphoid cells.Nature. 2013; 494: 261-265Crossref PubMed Scopus (520) Google Scholar). While it was recognized some time ago that T and B lymphocytes infiltrate adipose tissue and that their representation correlates with adiposity (Caspar-Bauguil et al., 2005Caspar-Bauguil S. Cousin B. Galinier A. Segafredo C. Nibbelink M. André M. Casteilla L. Pénicaud L. Adipose tissues as an ancestral immune organ: site-specific change in obesity.FEBS Lett. 2005; 579: 3487-3492Crossref PubMed Scopus (204) Google Scholar; Wu et al., 2007Wu H. Ghosh S. Perrard X.D. Feng L. Garcia G.E. Perrard J.L. Sweeney J.F. Peterson L.E. Chan L. Smith C.W. Ballantyne C.M. T-cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity.Circulation. 2007; 115: 1029-1038Crossref PubMed Scopus (513) Google Scholar; Rausch et al., 2008Rausch M.E. Weisberg S. Vardhana P. Tortoriello D.V. 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Nishimura et al. reported that CD8+ T cells are critical participants in obesity-induced adipose tissue and systemic inflammation (Nishimura et al., 2009Nishimura S. Manabe I. Nagasaki M. Eto K. Yamashita H. Ohsugi M. Otsu M. Hara K. Ueki K. Sugiura S. et al.CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity.Nat. Med. 2009; 15: 914-920Crossref PubMed Scopus (1621) Google Scholar). Their accumulation after introduction of a HFD appeared to precede that of macrophages, beginning within 2 weeks. Genetic ablation or monoclonal-antibody-mediated neutralization of CD8+ T cells in HFD-fed mice improved VAT inflammatory tone and systemic insulin sensitivity, under both protective and curative regimes, while not impacting body or VAT pad weight. Adoptive transfer of splenic CD8+ T cells largely reversed the effects of a CD8−/− mutation. Coculture experiments showed that CD8+ T cells can provoke macrophage migration and differentiation and, in turn, that adipocytes from obese, but not lean, mice can stimulate CD8+ cells. Consistent with the latter finding, HFD feeding resulted in a restriction of the repertoire of CD8+ T cells within VAT. Several of these findings were confirmed in an independent study (Yang et al., 2010Yang H. Youm Y.H. Vandanmagsar B. Ravussin A. Gimble J.M. Greenway F. Stephens J.M. Mynatt R.L. Dixit V.D. Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: implications for systemic inflammation and insulin resistance.J. Immunol. 2010; 185: 1836-1845Crossref PubMed Scopus (332) Google Scholar). The role of conventional CD4+ Th cells in organismal metabolism seems less clear-cut. Several groups have noted an enrichment of IFN-γ-producing Th1 cells in the VAT of obese individuals (Feuerer et al., 2009Feuerer M. Herrero L. Cipolletta D. Naaz A. Wong J. Nayer A. Lee J. Goldfine A.B. Benoist C. Shoelson S. Mathis D. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters.Nat. Med. 2009; 15: 930-939Crossref PubMed Scopus (1520) Google Scholar; Zúñiga et al., 2010Zúñiga L.A. Shen W.J. Joyce-Shaikh B. Pyatnova E.A. Richards A.G. Thom C. Andrade S.M. Cua D.J. Kraemer F.B. Butcher E.C. IL-17 regulates adipogenesis, glucose homeostasis, and obesity.J. Immunol. 2010; 185: 6947-6959Crossref PubMed Scopus (274) Google Scholar; Cheng et al., 2012Cheng X. Wang J. Xia N. Yan X.X. Tang T.T. Chen H. Zhang H.J. Liu J. Kong W. Sjöberg S. et al.A guanidine-rich regulatory oligodeoxynucleotide improves type-2 diabetes in obese mice by blocking T-cell differentiation.EMBO Mol Med. 2012; 4: 1112-1125Crossref PubMed Scopus (11) Google Scholar). And certainly there are abundant cells at that site potentially capable of antigen presentation to CD4+ T cells because they express both major histocompatibility complex (MHC) class II and costimulatory molecules—whether they be macrophages (Morris et al., 2013Morris D.L. Cho K.W. Delproposto J.L. Oatmen K.E. Geletka L.M. Martinez-Santibanez G. Singer K. Lumeng C.N. Adipose tissue macrophages function as antigen presenting cells and regulate adipose tissue CD4+ T cells in mice.Diabetes. 2013; (Published online March 14, 2013)https://doi.org/10.2337/db12-1404Crossref Scopus (161) Google Scholar) or adipocytes themselves (Deng et al., 2013Deng T. Lyon C.J. Minze L.J. Lin J. Zou J. Liu J.Z. Ren Y. Yin Z. Hamilton D.J. Reardon P.R. et al.Class II major histocompatibility complex plays an essential role in obesity-induced adipose inflammation.Cell Metab. 2013; 17: 411-422Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar; Meijer et al., 2011Meijer K. de Vries M. Al-Lahham S. Bruinenberg M. Weening D. Dijkstra M. Kloosterhuis N. van der Leij R.J. van der Want H. Kroesen B.J. et al.Human primary adipocytes exhibit immune cell function: adipocytes prime inflammation independent of macrophages.PLoS ONE. 2011; 6: e17154Crossref PubMed Scopus (157) Google Scholar). Given that IFN-γ is an important proinflammatory cytokine in obesity-induced inflammation and consequent metabolic abnormalities (Rocha et al., 2008Rocha V.Z. Folco E.J. Sukhova G. Shimizu K. Gotsman I. Vernon A.H. Libby P. Interferon-gamma, a Th1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity.Circ. Res. 2008; 103: 467-476Crossref PubMed Scopus (398) Google Scholar), Th1 cells are likely to join CD8+ T cells as important effector lymphocytes. On the other hand, Winer et al. have argued that Th2 cells exert a protective function
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