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Retinoic Acid-Related Orphan Receptors Α and Γ: Key Regulators of Lipid

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Retinoic Acid-Related Orphan Receptors Α and Γ: Key Regulators of Lipid REVIEW ARTICLE published: 25 January 2013 doi: 10.3389/fendo.2013.00001 Retinoic acid-related orphan receptors α and γ:key regulators of lipid/glucose metabolism, inflammation, and insulin sensitivity Anton M. Jetten*, Hong Soon Kang andYukimasaTakeda Cell Biology Section, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA Edited by: Retinoic acid-related orphan receptors RORα and RORγ play a regulatory role in Tsuguhito Ota, Kanazawa University, lipid/glucose homeostasis and various immune functions, and have been implicated Japan in metabolic syndrome and several inflammatory diseases. RORα-deficient mice are Reviewed by: protected against age- and diet-induced obesity, hepatosteatosis, and insulin resistance. Krzysztof W. Nowak, Pozan University of Life Sciences, Poland The resistance to hepatosteatosis in RORα-deficient mice is related to the reduced Venu Lagishetty, University of South expression of several genes regulating lipid synthesis, transport, and storage. Adipose Florida, USA tissue-associated inflammation, which plays a critical role in the development of insulin *Correspondence: resistance, is considerably diminished in RORα-deficient mice as indicated by the reduced Anton M. Jetten, Cell Biology Section, infiltration of M1 macrophages and decreased expression of many proinflammatory genes. Division of Intramural Research, National Institute of Environmental Deficiency in RORγ also protects against diet-induced insulin resistance by a mechanism Health Sciences, National Institutes that appears different from that in RORα deficiency. Recent studies indicated that RORs of Health, 111T.W. Alexander provide an important link between the circadian clock machinery and its regulation of Drive, Research Triangle Park, NC 27709, USA. metabolic genes and metabolic syndrome. As ligand-dependent transcription factors, e-mail: [email protected] RORs may provide novel therapeutic targets in the management of obesity and associated metabolic diseases, including hepatosteatosis, adipose tissue-associated inflammation, and insulin resistance. Keywords: retinoic acid-related orphan receptor, obesity, inflammation, adipose tissue, hepatosteatosis, diabetes, insulin-resistance, circadian rhythm INTRODUCTION RORα AND γ PROTEINS In the past 50 years, the occurrence of obesity has greatly increased The RORs alpha, beta, and gamma (RORα–γ or NR1F1–3) worldwide in both adults and children and has become a major constitute a subfamily of nuclear receptors that function as ligand- health-care concern in many countries. In the United States 30% dependent transcription factors (Jetten, 2004, 2009; Solt and of the population is considered obese, while more than 66% of Burris, 2012). RORs exhibit a domain structure typical of nuclear adults and almost 17% of children and adolescents are overweight receptors and contain an N-terminal domain, the function of (Browning et al., 2004; Ogden et al., 2012). Obesity is associated which has not yet been clearly defined, a highly conserved DNA- with an increased risk of several pathologies, including type 2 dia- binding domain (DBD) consisting of two zinc finger motifs, a LBD, betes, cardiovascular disease, and non-alcoholic fatty liver disease and a hinge domain spacing the DBD and LBD. By using differ- (NAFLD). Accumulating evidence indicates that networks regu- ent promoters and/or alternative splicing each ROR gene produces lating lipid metabolism and inflammation are highly integrated several isoforms that vary only in their N-terminal region. Some of and play a critical role in the development of these pathologies these isoforms exhibit a distinct tissue-specific pattern of expres- (Hotamisligil, 2006; Donath and Shoelson, 2011; Ouchi et al., sion and control different genes and biological processes. RORs 2011; Glass and Olefsky, 2012). Obesity leads to a systemic state regulate transcription by binding as monomers to ROR response of low-grade inflammation, particularly involving adipose tissue, elements (RORE), which consist of the core sequence “AGGTCA” that is causally involved in the development of insulin resis- preceded by an A/T-rich sequence, in the regulatory region of tance and other diseases. Blood levels of free fatty acids (FFA) target genes. The activation function (AF-2), localized at the C- are elevated in obesity and through their interaction with Toll- terminus within the LBD of RORs, is involved in the recruitment like receptor 4 (TLR4) FFA induce proinflammatory pathways in of co-activators or co-repressors that mediate the transcriptional macrophages and other cell types that may promote insulin resis- activation or repression by RORs. Recent studies have identified a tance (Samuel and Shulman, 2012). Recent studies demonstrated number of (ant)agonists that interact with the LBD of ROR and that retinoic acid-related orphan receptors (RORs) are among either activate or inhibit ROR transcriptional activity (Kallen et al., many factors that through their modulation of immune responses 2002; Huh and Littman, 2012; Solt and Burris, 2012). Interaction and lipid/glucose homeostasis regulate the development of inflam- with agonists induces a conformational change in the LBD that mation, metabolic syndrome, and insulin resistance (Jetten, 2009; allows release of the co-repressor complex and promotes assem- Solt and Burris, 2012). bly of a co-activator complex that mediates the transcriptional www.frontiersin.org January 2013 | Volume 4 | Article 1 | 1 “fendo-04-00001” — 2013/1/24 — 9:56 — page1—#1 Jetten et al. RORs in metabolicy syndrome activation by ROR, while the inverse happens for antagonists. fed a high fat diet (HFD) gain relatively less weight and exhibit These observations not only indicated that RORs function as a significantly lower total body fat index compared to wild-type ligand-dependent transcription factors, but also suggested that (WT) littermates on a HFD. Similarly, male RORαsg/sg mice were RORs might be potential therapeutic targets to treat disease. also protected against age-induced obesity. Adipose tissue is the main site of storage of excess energy that is stored in the form of RORs AS REGULATORS OF SEVERAL IMMUNE PROCESSES triglycerides in single large lipid droplets. The reduced adiposity RORα and RORγ are important regulators of several diverse in RORαsg/sg mice was largely related to smaller adipocyte size due immune functions. RORγ-deficient mice lack lymph nodes and to diminished deposition of triglycerides. Peyer’s patches indicating that it is essential for lymph node devel- RORα, particularly the RORα4 isoform, has been shown to be opment (Kurebayashi et al., 2000; Sun et al., 2000). Recent studies highly expressed in WAT and to be induced during differentiation demonstrated that RORα and the RORγt isoform play a key role in of D1 and 3T3-L1 preadipocytes (Austin et al., 1998). Overexpres- T cell lineage determination (Ivanov et al., 2006; Yang et al., 2008; sion of RORα in preadipocytes inhibits adipocyte differentiation Jetten, 2009). The RORγt isoform in particular and to a lesser (Duez et al., 2009; Ohoka et al., 2009). This appears to be mediated extent RORα, is required for the differentiation of naïve T cells through a direct interaction of RORα with CCAAT/enhancer- into interleukin 17 (IL-17) producing T helper 17 (Th17) cells. binding protein β (C/EBPβ) that results in the inhibition of the IL-17A expression is directly regulated by RORs through their recruitment of the co-activator CBP and repression of C/EBPβ interaction with ROREs in the Il17 promoter (Yang et al., 2008). transcriptional activity. These studies suggest that RORα has a Proinflammatory Th17 cells and IL-17 have been implicated in negative regulatory role in adipocyte differentiation. This func- several autoimmune diseases and other inflammatory disorders. tion, however, does not explain the reduced adiposity observed in Deficiency in RORγtorbothRORα/γ receptors has been shown to RORα-deficient mice. greatly inhibit the generation of Th17 cells and the development Obesity is a consequence of an imbalance between energy of experimental encephalomyelitis in mice. In addition, mice defi- intake and expenditure (Glass and Olefsky, 2012; Samuel and cient in RORα or RORγ displayed a diminished susceptibility to Shulman, 2012). However, the decrease in diet-induced adipos- allergen-induced lung inflammation and collagen-induced arthri- ity in RORαsg/sg mice was found not to be due to reduced food tis (Jaradat et al., 2006; Tilley et al., 2007) and polymorphisms intake or increased fecal lipid excretion. Indirect calorimetric in RORα have been associated with increased susceptibility to analysis showed that VO2,VCO2, and heat generation were signif- asthma (Ramasamy et al., 2012). A recent study identified a role for icantly enhanced in RORαsg/sg mice on a HFD (Kang et al., 2011). RORα in the generation of natural helper (NH) cells (Halim et al., This suggested that elevated energy expenditure might at least in 2012). RORα-deficient, but not RORγ-deficient, mice lack NH part be responsible for the reduced weight gain and resistance to cells. NH cell-deficient mice generated by RORα-deficient bone hepatosteatosis and insulin insensitivity in RORαsg/sg mice. marrow transplantation exhibited normal Th2 cell responses, but failed to develop acute lung inflammation in response to a pro- RORα AND WAT-ASSOCIATED INFLAMMATION tease allergen. These findings might at least in part explain the In addition to functioning
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