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• W2784241489 abstract "The worldwide obesity epidemic has emerged as a major cause of insulin resistance and Type 2 diabetes. Chronic tissue inflammation is a well-recognized feature of obesity, and the field of immunometabolism has witnessed many advances in recent years. Here, we review the major features of our current understanding with respect to chronic obesity-related inflammation in metabolic tissues and focus on how these inflammatory changes affect insulin sensitivity, insulin secretion, food intake, and glucose homeostasis. There is a growing appreciation of the varied and sometimes integrated crosstalk between cells within a tissue (intraorgan) and tissues within an organism (interorgan) that supports inflammation in the context of metabolic dysregulation. Understanding these pathways and modes of communication has implications for translational studies. We also briefly summarize the state of this field with respect to potential current and developing therapeutics. The worldwide obesity epidemic has emerged as a major cause of insulin resistance and Type 2 diabetes. Chronic tissue inflammation is a well-recognized feature of obesity, and the field of immunometabolism has witnessed many advances in recent years. Here, we review the major features of our current understanding with respect to chronic obesity-related inflammation in metabolic tissues and focus on how these inflammatory changes affect insulin sensitivity, insulin secretion, food intake, and glucose homeostasis. There is a growing appreciation of the varied and sometimes integrated crosstalk between cells within a tissue (intraorgan) and tissues within an organism (interorgan) that supports inflammation in the context of metabolic dysregulation. Understanding these pathways and modes of communication has implications for translational studies. We also briefly summarize the state of this field with respect to potential current and developing therapeutics. The prevalence of type 2 diabetes mellitus (T2DM) is rapidly increasing on a global basis and has now reached epidemic proportions. The etiology of T2DM involves both insulin resistance and β-cell dysfunction, and one typically needs both defects in order to develop the full hyperglycemic diabetic state (referred to as the two-hit hypothesis) (Defronzo, 2009Defronzo R.A. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus.Diabetes. 2009; 58: 773-795Crossref PubMed Scopus (1282) Google Scholar, Halban et al., 2014Halban P.A. Polonsky K.S. Bowden D.W. Hawkins M.A. Ling C. Mather K.J. Powers A.C. Rhodes C.J. Sussel L. Weir G.C. β-cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment.Diabetes Care. 2014; 37: 1751-1758Crossref PubMed Scopus (145) Google Scholar, Olefsky and Glass, 2010Olefsky J.M. Glass C.K. Macrophages, inflammation, and insulin resistance.Annu. Rev. Physiol. 2010; 72: 219-246Crossref PubMed Scopus (1339) Google Scholar). Obesity is far and away the most common cause of insulin resistance in man; therefore, it is the ongoing obesity epidemic that is driving the parallel rise in the incidence of T2DM (Olefsky and Glass, 2010Olefsky J.M. Glass C.K. Macrophages, inflammation, and insulin resistance.Annu. Rev. Physiol. 2010; 72: 219-246Crossref PubMed Scopus (1339) Google Scholar). While insulin resistance and β-cell dysfunction co-exist in the great majority of T2DM patients, the relative contribution and temporal appearance of these two defects varies across different patients and populations. Chronic obesity-associated inflammation, particularly in adipose tissue and liver, is a widely reported contributor to insulin resistance (Hotamisligil, 2017Hotamisligil G.S. Inflammation, metaflammation and immunometabolic disorders.Nature. 2017; 542: 177-185Crossref PubMed Scopus (149) Google Scholar), and recent evidence indicates that inflammation is also an important etiologic component of β-cell dysfunction in T2DM (Eguchi and Nagai, 2017Eguchi K. Nagai R. Islet inflammation in type 2 diabetes and physiology.J. Clin. Invest. 2017; 127: 14-23Crossref PubMed Scopus (24) Google Scholar). While there are many potential contributing mechanisms to both insulin resistance and β-cell dysfunction, in this review, we will focus our attention primarily on the role of chronic tissue inflammation in these metabolic defects. There are already many excellent recent reviews covering other potential non-inflammatory causes of insulin resistance and β-cell dysfunction (Czech, 2017Czech M.P. Insulin action and resistance in obesity and type 2 diabetes.Nat. Med. 2017; 23: 804-814Crossref PubMed Scopus (50) Google Scholar, Newgard, 2017Newgard C.B. Metabolomics and Metabolic Diseases: Where Do We Stand?.Cell Metab. 2017; 25: 43-56Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, Samuel and Shulman, 2016Samuel V.T. Shulman G.I. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux.J. Clin. Invest. 2016; 126: 12-22Crossref PubMed Scopus (217) Google Scholar). Several tissues or organs can make independent contributions to the etiology of T2DM. Chronic inflammation in the liver, muscle, adipose tissue, CNS, and gastrointestinal (GI) tract plays a role in achieving the final insulin-resistant, hyperglycemic diabetic state. This is depicted in Figure 1, which shows a variety of interconnections comprising an extensive interorgan crosstalk network. There are two aspects of consideration of immunometabolism. One is the effect of inflammation and immune responses on the control of systemic metabolism. The other focuses on metabolism within immune cells. Clearly, metabolic changes in immune cells have important effects on the function of these cell types (O’Neill et al., 2016O’Neill L.A. Kishton R.J. Rathmell J. A guide to immunometabolism for immunologists.Nat. Rev. Immunol. 2016; 16: 553-565Crossref PubMed Scopus (266) Google Scholar, Puleston et al., 2017Puleston D.J. Villa M. Pearce E.L. Ancillary Activity: Beyond Core Metabolism in Immune Cells.Cell Metab. 2017; 26: 131-141Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Here, we focus on immunometabolism as it relates to the effects of chronic inflammation on metabolic events and will also discuss future directions in this rapidly growing area. The role of subacute chronic inflammation, particularly in adipose tissue and liver, has been widely studied with respect to its role in systemic insulin resistance (Hotamisligil, 2017Hotamisligil G.S. Inflammation, metaflammation and immunometabolic disorders.Nature. 2017; 542: 177-185Crossref PubMed Scopus (149) Google Scholar). Recent evidence has also pointed toward the contribution of immune cell inflammation in islets in β-cell dysfunction (Eguchi and Nagai, 2017Eguchi K. Nagai R. Islet inflammation in type 2 diabetes and physiology.J. Clin. Invest. 2017; 127: 14-23Crossref PubMed Scopus (24) Google Scholar). With respect to both of these metabolic defects, obesity has emerged as an underlying etiology. Anti-diabetic effects of anti-inflammatory treatments (e.g., salicylate and berberine) have been known for over 100 years (Ebstein, 1876Ebstein W. Zur therapie des Diabetes mellitus, insbesondere über die Anwendung des salicylsauren Natron bei demselben.Berliner Klinische Wochenschrift. 1876; 13: 337-340Google Scholar, Lee et al., 2006Lee Y.S. Kim W.S. Kim K.H. Yoon M.J. Cho H.J. Shen Y. Ye J.M. Lee C.H. Oh W.K. Kim C.T. et al.Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states.Diabetes. 2006; 55: 2256-2264Crossref PubMed Scopus (649) Google Scholar, Yuan et al., 2001Yuan M. Konstantopoulos N. Lee J. Hansen L. Li Z.W. Karin M. Shoelson S.E. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta.Science. 2001; 293: 1673-1677Crossref PubMed Scopus (1431) Google Scholar). However, over the last couple of decades, we have begun to understand the underlying cellular and physiologic mechanisms of how obesity-associated inflammation induces insulin resistance and glucose intolerance. The first studies to establish a concrete mechanistic link between inflammation and insulin resistance focused on tumor necrosis factor-α (TNF-α). In 1989, Grunfeld and Feingold observed that treatment of rodents with TNF-α led to adverse metabolic events, including increased serum glucose levels (Feingold et al., 1989Feingold K.R. Soued M. Staprans I. Gavin L.A. Donahue M.E. Huang B.J. Moser A.H. Gulli R. Grunfeld C. Effect of tumor necrosis factor (TNF) on lipid metabolism in the diabetic rat. Evidence that inhibition of adipose tissue lipoprotein lipase activity is not required for TNF-induced hyperlipidemia.J. Clin. Invest. 1989; 83: 1116-1121Crossref PubMed Google Scholar). An additional seminal paper in the field discovered that TNF-α levels are elevated in adipose tissue of obese rodents and that TNF-α treatment causes insulin resistance in mice by activating IκB kinase β (IKKβ), while neutralization of circulating TNF-α improves insulin sensitivity (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 Google Scholar, Yuan et al., 2001Yuan M. Konstantopoulos N. Lee J. Hansen L. Li Z.W. Karin M. Shoelson S.E. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta.Science. 2001; 293: 1673-1677Crossref PubMed Scopus (1431) Google Scholar). Activation of other inflammatory kinases, such as Jun amino-terminal kinases (JNKs) is also a feature of the chronic obesity-induced tissue inflammatory state, and genetic ablation of JNK also leads to protection from obesity-induced inflammation and insulin resistance (Hirosumi et al., 2002Hirosumi J. Tuncman G. Chang L. Görgün C.Z. Uysal K.T. Maeda K. Karin M. Hotamisligil G.S. A central role for JNK in obesity and insulin resistance.Nature. 2002; 420: 333-336Crossref PubMed Scopus (2148) Google Scholar). Increased proinflammatory signaling has subsequently been observed in the three classical insulin target tissues (fat, liver, and muscle), as well as in islets, the CNS, and the GI tract (Cai et al., 2005Cai D. Yuan M. Frantz D.F. Melendez P.A. Hansen L. Lee J. Shoelson S.E. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.Nat. Med. 2005; 11: 183-190Crossref PubMed Scopus (1418) Google Scholar, De Souza et al., 2005De Souza C.T. Araujo E.P. Bordin S. Ashimine R. Zollner R.L. Boschero A.C. Saad M.J. Velloso L.A. Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus.Endocrinology. 2005; 146: 4192-4199Crossref PubMed Scopus (545) Google Scholar, Fink et al., 2014Fink L.N. Costford S.R. Lee Y.S. Jensen T.E. Bilan P.J. Oberbach A. Blüher M. Olefsky J.M. Sams A. Klip A. Pro-inflammatory macrophages increase in skeletal muscle of high fat-fed mice and correlate with metabolic risk markers in humans.Obesity (Silver Spring). 2014; 22: 747-757Crossref PubMed Scopus (62) Google Scholar, 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 Google Scholar, Lee et al., 2011bLee Y.S. Li P. Huh J.Y. Hwang I.J. Lu M. Kim J.I. Ham M. Talukdar S. Chen A. Lu W.J. et al.Inflammation is necessary for long-term but not short-term high-fat diet-induced insulin resistance.Diabetes. 2011; 60: 2474-2483Crossref PubMed Scopus (220) Google Scholar, Maedler et al., 2002Maedler K. Sergeev P. Ris F. Oberholzer J. Joller-Jemelka H.I. Spinas G.A. Kaiser N. Halban P.A. Donath M.Y. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets.J. Clin. Invest. 2002; 110: 851-860Crossref PubMed Scopus (811) 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 (5595) Google Scholar, Winer et al., 2017Winer D.A. Winer S. Dranse H.J. Lam T.K. Immunologic impact of the intestine in metabolic disease.J. Clin. Invest. 2017; 127: 33-42Crossref PubMed Scopus (2) Google Scholar, 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 (4043) Google Scholar). While most of the direct evidence that inflammation is a key cause of insulin resistance and impaired glucose metabolism in obesity stems from rodent studies, there are several ex vivo studies with primary human adipocytes, hepatocytes, skeletal muscle (SM) cells, and islets that also support the idea that inflammation can cause decreased insulin sensitivity and impaired insulin secretion (Austin et al., 2008Austin R.L. Rune A. Bouzakri K. Zierath J.R. Krook A. siRNA-mediated reduction of inhibitor of nuclear factor-kappaB kinase prevents tumor necrosis factor-alpha-induced insulin resistance in human skeletal muscle.Diabetes. 2008; 57: 2066-2073Crossref PubMed Scopus (59) Google Scholar, Dietze et al., 2002Dietze D. Koenen M. Röhrig K. Horikoshi H. Hauner H. Eckel J. Impairment of insulin signaling in human skeletal muscle cells by co-culture with human adipocytes.Diabetes. 2002; 51: 2369-2376Crossref PubMed Google Scholar, Löfgren et al., 2000Löfgren P. van Harmelen V. Reynisdottir S. Näslund E. Rydén M. Rössner S. Arner P. Secretion of tumor necrosis factor-alpha shows a strong relationship to insulin-stimulated glucose transport in human adipose tissue.Diabetes. 2000; 49: 688-692Crossref PubMed Google Scholar, Maedler et al., 2002Maedler K. Sergeev P. Ris F. Oberholzer J. Joller-Jemelka H.I. Spinas G.A. Kaiser N. Halban P.A. Donath M.Y. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets.J. Clin. Invest. 2002; 110: 851-860Crossref PubMed Scopus (811) Google Scholar, Pardo Marqués et al., 2016Pardo Marqués V. González-Rodríguez A. Valverde A.M. New therapeutic targets for the treatment of insulin resistance based on the paracrine cross-talk between hepatocytes and Kupffer cells.Anales de la Real Academia Nacional de Farmacia. 2016; 82: 200-209Google Scholar). However, the overall concept for a causal role of inflammation in insulin resistance still remains to be validated in man. Adipose tissue can comprise white, brown, or beige adipocytes. White adipocytes are specialized to store excessive energy in the form of triglycerides and to release fatty acids (FAs) in times of energy deficiency. White adipose tissue (WAT) also releases a variety of secretory peptides and lipid metabolites that signal to other tissues (Deng and Scherer, 2010Deng Y. Scherer P.E. Adipokines as novel biomarkers and regulators of the metabolic syndrome.Ann. N Y Acad. Sci. 2010; 1212: E1-E19Crossref PubMed Google Scholar, Glass and Olefsky, 2012Glass C.K. Olefsky J.M. Inflammation and lipid signaling in the etiology of insulin resistance.Cell Metab. 2012; 15: 635-645Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar, Smith and Kahn, 2016Smith U. Kahn B.B. Adipose tissue regulates insulin sensitivity: role of adipogenesis, de novo lipogenesis and novel lipids.J. Intern. Med. 2016; 280: 465-475Crossref PubMed Scopus (39) Google Scholar), contributing to systemic energy and glucose homeostasis. In contrast to WAT, the major function of brown and beige adipocytes is to generate heat under cold stress, which is well reviewed elsewhere (Kajimura et al., 2015Kajimura S. Spiegelman B.M. Seale P. Brown and Beige Fat: Physiological Roles beyond Heat Generation.Cell Metab. 2015; 22: 546-559Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). Therefore, in this section, we will focus on inflammation and WAT. Adipose tissue inflammation occurs as early as 3–7 days after feeding high-fat diet (HFD) in mice and gradually increases, contributing to systemic insulin resistance and glucose intolerance (Lee et al., 2011bLee Y.S. Li P. Huh J.Y. Hwang I.J. Lu M. Kim J.I. Ham M. Talukdar S. Chen A. Lu W.J. et al.Inflammation is necessary for long-term but not short-term high-fat diet-induced insulin resistance.Diabetes. 2011; 60: 2474-2483Crossref PubMed Scopus (220) Google Scholar). During obesity, different types of both innate and adaptive immune cells accumulate in adipose tissue with increased adipocyte chemokine production (Lackey and Olefsky, 2016Lackey D.E. Olefsky J.M. Regulation of metabolism by the innate immune system.Nat. Rev. Endocrinol. 2016; 12: 15-28Crossref PubMed Scopus (153) Google Scholar) and impaired macrophage emigration from adipose tissue (Ramkhelawon et al., 2014Ramkhelawon B. Hennessy E.J. Ménager M. Ray T.D. Sheedy F.J. Hutchison S. Wanschel A. Oldebeken S. Geoffrion M. Spiro W. et al.Netrin-1 promotes adipose tissue macrophage retention and insulin resistance in obesity.Nat. Med. 2014; 20: 377-384Crossref PubMed Scopus (75) Google Scholar), preventing resolution of inflammation. Of the adipose tissue immune cells, macrophages are the most abundant and can comprise up to 40% of all stromal vascular cells in obese adipose tissue (Lumeng et al., 2007Lumeng 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 (2214) Google Scholar). They are a major source of proinflammatory cytokines, which have the potential to cause local and systemic insulin resistance (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 (4043) Google Scholar). Indeed, numerous studies have shown that genetic manipulations that impair macrophage proinflammatory pathway activity protect against obesity-induced insulin resistance and glucose intolerance (Lackey and Olefsky, 2016Lackey D.E. Olefsky J.M. Regulation of metabolism by the innate immune system.Nat. Rev. Endocrinol. 2016; 12: 15-28Crossref PubMed Scopus (153) Google Scholar). The intracellular events leading to impaired insulin signaling after proinflammatory stimulation have been well studied and include activation of inhibitor of κB kinases (IKKs), nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), JNKs, and increased oxidative stress (Lackey and Olefsky, 2016Lackey D.E. Olefsky J.M. Regulation of metabolism by the innate immune system.Nat. Rev. Endocrinol. 2016; 12: 15-28Crossref PubMed Scopus (153) Google Scholar). These pathways all trigger transcriptional activation of proinflammatory genes, decreased expression of adipocyte-specific genes, suppression of insulin-receptor action, and inhibitory phosphorylation or nitrosylation of insulin-signaling molecules (Hotamisligil, 2017Hotamisligil G.S. Inflammation, metaflammation and immunometabolic disorders.Nature. 2017; 542: 177-185Crossref PubMed Scopus (149) Google Scholar, Xing et al., 1997Xing H. Northrop J.P. Grove J.R. Kilpatrick K.E. Su J.L. Ringold G.M. TNF alpha-mediated inhibition and reversal of adipocyte differentiation is accompanied by suppressed expression of PPARgamma without effects on Pref-1 expression.Endocrinology. 1997; 138: 2776-2783Crossref PubMed Scopus (0) Google Scholar). Tissue macrophages are often classified based on their inflammatory state, with classically activated M1 proinflammatory macrophages versus alternatively activated M2 anti-inflammatory cells. While the designations M1 and M2 are often used to categorize macrophages, these definitions largely derive from in vitro studies (Sica and Mantovani, 2012Sica A. Mantovani A. Macrophage plasticity and polarization: in vivo veritas.J. Clin. Invest. 2012; 122: 787-795Crossref PubMed Scopus (2077) Google Scholar). In the in vivo setting, it is likely that adipose tissue macrpophages (ATMs) exist across a polarization spectrum from the most inflammatory to anti-inflammatory phenotypes (Kratz et al., 2014Kratz M. Coats B.R. Hisert K.B. Hagman D. Mutskov V. Peris E. Schoenfelt K.Q. Kuzma J.N. Larson I. Billing P.S. et al.Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages.Cell Metab. 2014; 20: 614-625Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, Li et al., 2010Li P. Lu M. Nguyen M.T. Bae E.J. Chapman J. Feng D. Hawkins M. Pessin J.E. Sears D.D. Nguyen A.K. et al.Functional heterogeneity of CD11c-positive adipose tissue macrophages in diet-induced obese mice.J. Biol. Chem. 2010; 285: 15333-15345Crossref PubMed Scopus (133) Google Scholar, Lumeng et al., 2008Lumeng C.N. DelProposto J.B. Westcott D.J. Saltiel A.R. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes.Diabetes. 2008; 57: 3239-3246Crossref PubMed Scopus (414) 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 (591) Google Scholar). Thus, the terms M1-like and M2-like are used to generally depict the proinflammatory state of recruited ATMs versus the anti-inflammatory state of resident ATMs. Most ATMs express the surface markers CD11b and F4/80. In obesity, the majority of recruited ATMs are also positive for CD11c, and ATMs expressing this marker typically exhibit increased expression of proinflammatory genes (Lumeng et al., 2007Lumeng 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 (2214) 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 (591) Google Scholar). While ATMs are the major effector cell type generating factors that cause insulin resistance, changes in several other innate immune cell types in obese adipose tissue contribute to initiation and/or progression of adipose tissue inflammation. For example, in lean adipose tissue, innate lymphoid type 2 (ILC2) cells secrete Th2 cytokines IL-5 and IL-13, stimulating eosinophil chemotaxis and maturation (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 (324) Google Scholar, Nussbaum et al., 2013Nussbaum J.C. Van Dyken S.J. von Moltke J. Cheng L.E. Mohapatra A. Molofsky A.B. Thornton E.E. Krummel M.F. Chawla A. Liang H.E. Locksley R.M. Type 2 innate lymphoid cells control eosinophil homeostasis.Nature. 2013; 502: 245-248Crossref PubMed Scopus (331) Google Scholar). Activated eosinophils can repress adipose tissue inflammation by releasing IL-4 and IL-13, key drivers of the M2-like macrophage polarization state (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 (612) Google Scholar). During obesity, representation of ILC2 cells and eosinophils in adipose tissue declines with increasing adiposity, which can enhance obesity-induced inflammatory activation of ATMs (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 (324) Google Scholar). On the other hand, neutrophils are among the first responders recruited to adipose tissue in mice on HFD. They release neutrophil elastase (NE), which impairs insulin signaling by promoting IRS-1 degradation (Talukdar et al., 2012Talukdar S. Oh D.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 (360) Google Scholar). Similar to ILC2 cells, ILC1 cells also reside in lean adipose tissue, but their number increases in obesity, contributing to adipose tissue inflammation (Boulenouar et al., 2017Boulenouar S. Michelet X. Duquette D. Alvarez D. Hogan A.E. Dold C. O’Connor D. Stutte S. Tavakkoli A. Winters D. et al.Adipose Type One Innate Lymphoid Cells Regulate Macrophage Homeostasis through Targeted Cytotoxicity.Immunity. 2017; 46: 273-286Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, Lee et al., 2016Lee B.C. Kim M.S. Pae M. Yamamoto Y. Eberlé D. Shimada T. Kamei N. Park H.S. Sasorith S. Woo J.R. et al.Adipose Natural Killer Cells Regulate Adipose Tissue Macrophages to Promote Insulin Resistance in Obesity.Cell Metab. 2016; 23: 685-698Abstract Full Text Full Text PDF PubMed Google Scholar, Theurich et al., 2017Theurich S. Tsaousidou E. Hanssen R. Lempradl A.M. Mauer J. Timper K. Schilbach K. Folz-Donahue K. Heilinger C. Sexl V. et al.IL-6/Stat3-Dependent Induction of a Distinct, Obesity-Associated NK Cell Subpopulation Deteriorates Energy and Glucose Homeostasis.Cell Metab. 2017; 26: 171-184Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar). Several types of adaptive immune cells are also involved in obesity-induced adipose tissue inflammation. CD3+ T cells comprise the largest adipose-tissue immune-cell population next to macrophages, and their number is increased in HFD/obese mice (McNelis and Olefsky, 2014McNelis J.C. Olefsky J.M. Macrophages, immunity, and metabolic disease.Immunity. 2014; 41: 36-48Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar). T cells can be categorized into two groups, depending on their phenotypic expression of the surface coreceptors CD4 or CD8. Adipose tissue CD8+ T cell content is increased in obesity, and these cells release factors facilitating macrophage differentiation and chemotaxis (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 (1096) Google Scholar). CD4+ T cells can be further subcategorized based on their functional profile into proinflammatory T helper (Th)1 and Th17 cells, anti-inflammatory Th2 cells, and T regulatory (Treg) cells. The number of CD3+CD4+ Th1 cells is increased in obesity, and they contribute to adipose tissue inflammation by producing interferon γ (IFNγ) (Winer et al., 2009Winer S. Chan Y. Paltser G. Truong D. Tsui H. Bahrami J. Dorfman R. Wang Y. Zielenski J. Mastronardi F. et al.Normalization of obesity-associated insulin resistance through immunotherapy.Nat. Med. 2009; 15: 921-929Crossref PubMed Scopus (760) Google Scholar). In contrast, the number of CD3+CD4+ Th2 cells is decreased in obese adipose tissue (Winer et al., 2009Winer S. Chan Y. Paltser G. Truong D. Tsui H. Bahrami J. Dorfman R. Wang Y. Zielenski J. Mastronardi F. et al.Normalization of obesity-associated insulin resistance through immunotherapy.Nat. Med. 2009; 15: 921-929Crossref PubMed Scopus (760) Google Scholar). Treg cells (CD3+CD4+FOXP3+) are a small subset of CD4+ T lymphocytes (5%–20% of CD3+CD4+ cells) that can control the activity of other T cells or the innate immune system, inhibiting inappropriate inflammation. Lean adipose tissue harbors a unique Treg population characterized by high peroxisome proliferator-activated receptor γ (PPARγ) expression, and these Tregs play an important role in maintaining adipose-tissue inflammatory tone and insulin sensitivity (Bapat et al., 2015Bapat S.P. Myoung Suh J. Fang S. Liu S. Zhang Y. Cheng A. Zhou C. Liang Y. LeBlanc M. Liddle C. et al.Depletion of fat-resident Treg cells prevents age-associated insulin resistance.Nature. 2015; 528: 137-141Crossref PubMed Scopus (9) Google Scholar, 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 (974) Google Scholar). In obesity, the number or proportion of adipose tissue Treg cells declines, contributing to increased adipose tissue inflammation and insulin resistance (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;" @default.
• W2784241489 created "2018-01-26" @default.
• W2784241489 creator A5002663946 @default.
• W2784241489 creator A5018746393 @default.
• W2784241489 creator A5091832115 @default.
• W2784241489 date "2018-01-01" @default.
• W2784241489 modified "2023-10-17" @default.
• W2784241489 title "An Integrated View of Immunometabolism" @default.
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