Immune Modulation of Brown(ing) Adipose Tissue in Obesity

RE VIE W Immune Modulation of Brown(ing) Adipose Tissue in Obesity Susan M. van den Berg,1 Andrea D. van Dam,2,3 Patrick C. N. Rensen,2,3 Menno P. J. de Winther,1,4* and Esther Lutgens1,4* 1 Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Centre, University of Amsterdam, 1105AZ The Netherlands; 2Department of Medicine, Division of Endocrinology, and 3Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333ZA Leiden, The Netherlands; and 4Institute for Cardiovascular Prevention, Ludwig Maximilians University of Munich, 80539 Munich, Germany Obesity is associated with a variety of medical conditions such as type 2 diabetes and cardiovascular diseases and is therefore responsible for high morbidity and mortality rates. Increasing energy expenditure by brown adipose tissue (BAT) is a current novel strategy to reduce the excessive energy stores in obesity. Brown adipocytes burn energy to generate heat and are mainly activated upon cold exposure. As prolonged cold exposure is not a realistic therapy, researchers worldwide are searching for novel ways to activate BAT and/or induce beiging of white adipose tissue. Recently, the contribution of immune cells in the regulation of brown adipocyte activity and beiging of white adipose tissue has gained increased attention, with a prominent role for eosinophils and alternatively activated macrophages. This review discusses the rediscovery of BAT, presents an overview of modes of activation and differentiation of beige and brown adipocytes, and describes the recently discovered immunological pathways that are key in mediating brown/beige adipocyte development and function. Interventions in immunological pathways harbor the potential to provide novel strategies to increase beige and brown adipose tissue activity as a therapeutic target for obesity. (Endocrine Reviews 38: 46–68, 2017) I. Introduction II. Brown Adipose Tissue A. Brown adipose tissue regulates adaptive thermogenesis by mitochondrial uncoupling B. White, beige, and brown adipocytes C. BAT activity and obesity: what we have learned from mouse models Genetic models of decreased BAT activity Increasing BAT activity improves metabolism in mice BAT activation and atherosclerosis III. BAT and Obesity in Humans A. Presence of active BAT in human adults B. BAT activity and obesity IV. Chronic Low-Grade Inflammation in Obesity A. Dysfunctional adipocytes in WAT attract immune cells B. Inflammation in obese white adipose tissue Myeloid cell recruitment into WAT Lymphoid cell infiltration in WAT C. The immune system in brown and beige adipose tissue Inflammatory mediators in BAT BAT activation and beiging of WAT: role of the immune system Cytokines Chemokines Lipokines ISSN Print 0163-769X ISSN Online 1945-7189 Printed in USA Copyright © 2017 by the Endocrine Society Received 24 May 2016. Accepted 14 November 2016. First Published Online 16 November 2016 *These authors contributed equally to this work. Abbreviations: AMPK, AMP-activated protein kinase; ATP, adenosine triphosphate; BAT, brown adipose tissue; BMI, body mass index; cAMP, cyclic adenosine monophosphate; CT, computed tomography; DIO, diet-induced obesity; FDG, 18F-fluorodeoxy-glucose; HFD, high-fat diet; IFNg, interferon g; IL, interleukin; ILC2, type 2 innate lymphoid cell; IRF, interferon regulatory factor; LDLR, low-density lipoprotein receptor; LPL, lipoprotein lipase; MetEnk, methionine-enkephalin; mRNA, messenger RNA; Myf5, myogenic factor 5; PAHSA, palmitic acid esters of hydroxyl-stearic acid; Pax3, paired box 3; PDGFRa, plateletderived growth factor receptor a; PET, positron emission tomography; PGC-1a, proliferatoractivated receptor g coactivator 1a; PPARg, peroxisome proliferator-activated receptor g; PRDM16, PR domain zinc finger protein 16; TH, tyrosine hydroxylase; TLR, Toll-like receptor; TNF, tumor necrosis factor a; T-reg, regulatory T cell; TRL, triglyceride-rich lipoprotein; UCP1, uncoupling protein 1; VEGF, vascular endothelial growth factor; WAT, white adipose tissue. 46 press.endocrine.org/journal/edrv Endocrine Reviews, February 2017, 38(1):46–68 doi: 10.1210/er.2016-1066 doi: 10.1210/er.2016-1066 press.endocrine.org/journal/edrv 47 II. Brown Adipose Tissue ESSENTIAL POINTS · · · · · Cold stimulates brown adipose tissue (BAT) to increase energy expenditure in mice, so brown adipocytes are an intriguing target for the control of whole-body energy balance, adiposity, and obesity A. Brown adipose tissue regulates adaptive thermogenesis by mitochondrial uncoupling Whereas white adipose tissue (WAT) is specialized in the storage of energy, In mice, a variety of stimuli other than cold can activate BAT but also promote beiging; brown adipose tissue (BAT) plays a the development of brown-adipose-tissue-like cells within white adipose tissue, by central role in energy expenditure. Brown transdifferentiation or de novo from precursor cells adipocytes convert energy from glucose It is now clear that humans also have BAT reserves, although whitening of BAT can and fatty acids into heat via nonshivering occur in response to ageing, excessive energy storage, and other factors thermogenesis, which contributes to the maintenance of body temperature (7). An increase in BAT activity improves metabolism whereas a decrease is associated The regulation of body temperature is with metabolic dysfunction and obesity in mice crucial to ensure that cellular functions Obese white adipose tissue is characterized by the infiltration of immune cells which and physiological processes continue in initiates a state of chronic low-grade inflammation, but the immune system also plays cold environments (8). This regulation is an important role in the development, function, and activity of BAT and in beiging of particularly important in small organisms white adipose tissue with a relatively large surface area. Even Drugs that induce beiging of white adipose tissue or stimulate BAT via immunological newborns of large organisms have dispathways have the potential to treat obesity and its associated harmful sequelae, tinct depots of BAT that regress with including type 2 diabetes and cardiovascular disease increasing age. BAT in adult humans is most commonly present in the supraclavicular and neck region but also along the vertebrae and V. Concluding Remarks and Future Perspectives A. Translational challenges from mice to men aorta and near the kidneys (Fig. 1) (9). In rodents, the major B. Speculation on human BAT from an evolutionary BAT depot is found in the interscapular region, whereas perspective smaller depots include axillary BAT, cervical BAT, and C. Therapeutic potential perirenal and periaortic BAT (Fig. 1) (10, 11). D. Conclusion BAT is highly innervated by the sympathetic nervous system, and a well-structured vascularization enables the I. Introduction supply of oxygen and transport of heat. Brown adipocytes have (...truncated)