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Chronic Tissue Inflammation and Metabolic Disease Downloaded from genesdev.cshlp.org on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Chronic tissue inflammation and metabolic disease Yun Sok Lee and Jerrold Olefsky Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, La Jolla, California 92093, USA Obesity is the most common cause of insulin resistance, Although there are a number of potential, and some- and the current obesity epidemic is driving a parallel times overlapping, mechanisms that can contribute to in- rise in the incidence of T2DM. It is now widely recognized sulin resistance and β-cell dysfunction, in this current that chronic, subacute tissue inflammation is a major eti- review we focus on the role of chronic tissue inflamma- ologic component of the pathogenesis of insulin resis- tion in these metabolic defects. The reader is referred to tance and metabolic dysfunction in obesity. Here, we other excellent reviews on possible causes of insulin resis- summarize recent advances in our understanding of tance and β-cell dysfunction, independent of chronic tis- immunometabolism. We discuss the characteristics of sue inflammation (Halban et al. 2014; DeFronzo et al. chronic inflammation in the major metabolic tissues 2015; Czech 2017; Newgard 2017; Guilherme et al. and how obesity triggers these events, including a focus 2019; Kahn et al. 2019; Roden and Shulman 2019; Scherer on the role of adipose tissue hypoxia and macrophage-de- 2019; Alonge et al. 2021; Sangwung et al. 2020). rived exosomes. Last, we also review current and potential The interconnections between inflammation and meta- new therapeutic strategies based on immunomodulation. bolic dysfunction are often described by the term immu- nometabolism (Hotamisligil 2017). Immunometabolism includes the effects of immune cells on the regulation of Insulin resistance is a key feature of obesity and type 2 systemic metabolism, as well as the effects of metabolism diabetes mellitus (T2DM). Since obesity is the most com- within immune cells on inflammation. Both of these mon cause of insulin resistance in humans, the obesity ep- mechanisms are of importance, but in this review we fo- idemic is the major cause of the rising global incidence of cus our attention on the role of chronic inflammation in T2DM. In nondiabetic subjects with obesity, hyperinsuli- the etiology of disordered glucose homeostasis. nemia usually compensates for the underlying insulin re- Chronic inflammation in adipose tissue, the liver, the sistance, maintaining glucose homeostasis within normal central nervous system, the gastrointestinal (GI) tract, or near normal levels. When compensatory hyperinsuline- pancreatic islets, and muscle have all been described in mia fails and insulin levels decline due to development of obese/T2DM states, indicating the complex, multiorgan a β-cell defect, hyperglycemia and the typical T2DM state crosstalk network involved in these disorders. The gene- ensues, indicating that both insulin resistance and β-cell ral metabolic consequences of obesity-induced tissue in- dysfunction are needed for the full development of this flammation are summarized in Table 1. These concepts disease. In obesity, chronic tissue inflammation is a are mostly derived from mouse studies, and among all well-reported key contributor to decreased insulin sensi- these contributing tissues, adipose tissue inflammation tivity, particularly in adipose tissue and the liver. Howev- in obesity has been the most extensively studied. er, several recent reports have shown obesity-associated Although the contribution of chronic inflammation in inflammatory responses in pancreatic islets (Zhao et al. T2DM in obesity has been suggested for many years, in 2003; Warren et al. 2006; Ehses et al. 2007; Böni-Schnet- the past two decades a number of studies have been pub- zler et al. 2008; Richardson et al. 2009; Mahdi et al. lished, bringing out underlying physiologic and molecular 2012; Jourdan et al. 2013; Kamada et al. 2013; Butcher mechanisms as to how obesity-associated inflammation et al. 2014; Hasnain et al. 2014; Ying et al. 2019), suggest- leads to insulin resistance and glucose intolerance. One ing that chronic islet inflammation can also lead to β-cell of the earliest studies was reported by Grunfeld and Fein- dysfunction in the context of obese T2DM subjects. gold (Feingold et al. 1989) who showed that treatment of ro- dents with TNFα leads to hyperglycemia. An additional key early study showed increased TNFα levels in the adi- pose tissue of obese mice and showed that neutralization [Keywords: β-cell dysfunction; glucose intolerance; immunometabolism; inflammation; insulin resistance; macrophage; metaflammation] Corresponding author: [email protected] © 2021 Lee and Olefsky This article, published in Genes & Development, Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.346312. is available under a Creative Commons License (Attribution-NonCom- 120. Freely available online through the Genes & Development Open Ac- mercial 4.0 International), as described at http://creativecommons.org/li- cess option. censes/by-nc/4.0/. GENES & DEVELOPMENT 35:307–328 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/21; www.genesdev.org 307 Downloaded from genesdev.cshlp.org on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press Lee and Olefsky Table 1. The metabolic effects of obesity-associated tissue validated in humans, recent advances in genome-wide as- inflammation sociation studies (GWAS) suggest that inflammation might be causally related to the incidence of T2DM in hu- mans. While early GWASs showed that T2DM is associat- ed with genetic variations in genes associated with insulin secretion and β-cell function (McCarthy et al. 2010; Di- mas et al. 2014), later studies found that genes involved in peripheral insulin sensitivity and adipose tissue func- tion such as PPARG and KLF14 are also associated with the incidence of T2DM (Voight et al. 2010). Moreover, var- iations in genes regulating T-cell (e.g., PTPRJ and CMIP) or macrophage (e.g., MAEA) function or inflammatory sig- naling pathways (e.g., WWOX, MAP8IP1, IFNGR1, ST6GAL1, JAZF1, MAP3K1, MACROD1, NFE2L3, and TLR4) are also associated with the incidence of T2DM (Waeber et al. 2000; Kooner et al. 2011; Cho et al. 2012; Manning et al. 2012; Locke et al. 2015; Shungin et al. 2015; Flannick et al. 2019; Liao et al. 2019; Diedisheim et al. 2020). While more inclusive GWAS and whole- exome sequencing studies are being updated (Mahajan α of TNF ameliorates insulin resistance (Hotamisligil et al. et al. 2018; Flannick et al. 2019), many genetic variations 1993). Numerous studies have identified various molecules associated with the incidence of T2DM are found in non- within the inflammatory signaling cascade that can impair coding DNA regions. Moreover, heterogeneity in the eti- β insulin signaling, such as JNK, IKK , and various cytokines ology of T2DM (Philipson 2020) may dilute the (Xia et al. 2015; Goldfine and Shoelson 2017; Hotamisligil contribution of specific genetic variations to disease pa- 2017; Zhao et al. 2018; Donath et al. 2019; Hall et al. 2020). thology. One should take these factors into consideration Many reports have identified a mechanistic link between when interpreting GWAS results. chronic inflammation and insulin resistance in rodent studies by use of various genetic gain- and loss-of-function studies (Lee et al. 2018). For example, mice engineered to Inflammation in obesity globally deplete IKKβ, JNK, CCR2, or CCL2/MCP-1 show improved insulin sensitivity in obesity (Hirosumi et al. Adipose tissue 2002; Arkan et al. 2005; Weisberg et al. 2006). Adipocyte Chronic adipose tissue inflammation is a characteristic α or hepatocyte KO of JNK, HIF-1 , NEMO, or TLR4 also pro- feature of obesity, and two early studies published simul- duce enhanced insulin sensitivity (Sabio et al. 2008; Wun- taneously in 2003 (Weisberg et al. 2003; Xu et al. 2003) derlich et al. 2008; Jia et al. 2014; Lee et al. 2014). In showed that this was largely due to the increased accumu- contrast, adipocyte-specific overexpression of Ccl2 or lation of proinflammatory macrophages in both human Hif1a induces insulin resistance and glucose intolerance and mouse adipose tissue. Many subsequent reports on a normal chow diet (Kanda et al. 2006; Halberg et al. have documented this accumulation of adipose tissue 2009). Most importantly, a large number of macrophage macrophages (ATMs) in obese adipose tissue and have fur- (or hematopoietic cell)-specific KOs of inflammatory mol- ther characterized these macrophages with respect to sur- ecules have been reported that all lead to protection from face markers, biological effects, and transcriptomic insulin resistance and glucose intolerance (Saberi et al. phenotypes. In addition to macrophages, other innate 2009; Olefsky and Glass 2010; Han et al. 2013; Hill et al. and adaptive immune cell types participate in obese adi- 2014; Takikawa et al. 2016; Desai et al. 2017). However, pose tissue inflammation (summarized in Fig. 1). Howev- while there are a number of studies in human adipose tis- er, macrophages are the dominant cell type mediating sue (Lofgren et al. 2000; Fabbrini et al. 2013; Hill et al. insulin resistance and metabolic dysfunction in obese ad- 2018), the liver (Senn et al. 2002; Ghazarian et al. 2017), pri- ipose tissue. Thus, macrophages are the most abundant mary adipocytes (Liu et al. 1998), skeletal muscle (Austin immune cell type accumulating in obese adipose tissue et al. 2008), and pancreatic islets (Maedler et al. 2002) and liver. Moreover, these cells are the main immune cells that are supportive of this immunometabolism process secreting most of the inflammatory cytokines, galectin-3, (Pickup et al. 1997), the concept that chronic inflammation and exosomes (Weisberg et al. 2003; Zeyda et al. 2007; Li β causes insulin resistance and -cell dysfunction still re- et al. 2016; Ying et al. 2017a), and depletion of macrophag- mains to be validated in humans. es corrects insulin resistance and glucose tolerance in obese mice (Huang et al. 2010; Chatenoud et al.
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