Brown Adipose Tissue in Adult Humans: A Metabolic Renaissance

R E V I E W Brown Adipose Tissue in Adult Humans: A Metabolic Renaissance Paul Lee, Michael M. Swarbrick, and Ken K. Y. Ho School of Medicine (P.L., K.K.Y.H.), University of Queensland, and Department of Diabetes and Endocrinology (P.L., K.K.Y.H.), Princess Alexandra Hospital, Brisbane, Queensland 4107, Australia; and Diabetes and Obesity Program (M.M.S.), Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia and Faculty of Medicine (M.M.S.), School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia Brown adipose tissue (BAT) plays a key role in energy homeostasis and thermogenesis in animals, conferring protection against diet-induced obesity and hypothermia through the action of uncoupling protein 1 (UCP1). Recent metabolic imaging studies using positron emission tomography computerized tomography (PET-CT) scanning have serendipitously revealed significant depots of BAT in the cervical-supraclavicular regions, demonstrating persistence of BAT beyond infancy. Subsequent cold-stimulated PET-CT studies and direct histological examination of adipose tissues have demonstrated that BAT is highly prevalent in adult humans. BAT activity correlates positively with increment of energy expenditure during cold exposure and negatively with age, body mass index, and fasting glycemia, suggesting regulatory links between BAT, cold-induced thermogenesis, and energy metabolism. Human BAT tissue biopsies express UCP1 and harbor inducible precursors that differentiate into UCP1-expressing adipocytes in vitro. These recent discoveries represent a metabolic renaissance for human adipose biology, overturning previous belief that BAT had no relevance in adult humans. They also have implications for the understanding of the pathogenesis and treatment of obesity and its metabolic sequelae. (Endocrine Reviews 34: 413– 438, 2013) I. Introduction I. Introduction II. A Historical Perspective dipose tissue plays a central role in the interplay between nutrition, energy balance, and human health. There are 2 types of adipose tissue, white and brown. White adipose tissue (WAT) stores energy, whereas brown adipose tissue (BAT) dissipates it. Overnutrition and/or physical inactivity result in an excess of WAT, the hallmark of obesity. In contrast, BAT is thermogenic, a property conferred by the presence of a unique protein, uncoupling protein 1 (UCP1). Located in the inner mitochondrial membrane, UCP1 uncouples mitochondrial respiration, releasing energy as heat. This unique property protects animals from hypothermia (1). The traditional belief that BAT exists only in infants but not in adults has resulted in a paucity of research in humans. However, the discovery of fat with high metabolic activity in adults by functional imaging using positron emission tomography (PET) brought about a resurgence in A III. Characterisitics and Ontogeny A. Tissue characteristics B. Ontogeny IV. Physiology of BAT A. Location B. Prevalence C. Regulatory factors V. Metabolic Significance of BAT in Humans A. Insight from animals B. BAT activity and resting EE C. Relationship to adiposity VI. Implications for Human Health VII. Future Directions A. BAT detection and monitoring B. BAT genetics C. BAT-enhancing therapeutic strategies VIII. Conclusion Abbreviations: AR, adrenergic receptor; BAT, brown adipose tissue; BMI, body mass index; C/EBP, CCAAT/enhancer-binding protein; CIT, cold-induced thermogenesis; CT, computerized tomography; DIT, diet-induced thermogenesis; EE, energy expenditure; 18FDG, [18F]fluorodeoxyglucose; FGF21, fibroblast growth factor 21; IRT, infrared thermography; MR, magnetic resonance; PET, positron emission tomography; PGC-1␣, PPAR-␥ coactivator-1␣; PPAR-␥, peroxisome proliferator-activated receptor ␥; PRDM16, PRD1-BF-1-RIZ1 homologous domain containing protein-16; SNS, sympathetic nervous system; TH, thyroid hormone; UCP1, uncoupling protein 1; WAT, white adipose tissue. ISSN Print 0163-769X ISSN Online 1945-7189 Printed in U.S.A. Copyright © 2013 by The Endocrine Society Received October 31, 2012. Accepted January 17, 2013. First Published Online April 2, 2013 doi: 10.1210/er.2012-1081 Endocrine Reviews, June 2013, 34(3):413– 438 edrv.endojournals.org 413 414 Lee et al Brown Adipose Tissue in Adult Humans research interest on BAT identity, abundance, prevalence, regulation, and significance in humans (2–9). This review will cover 1) the characteristics and ontogeny of BAT, 2) its prevalence and regulation, 3) metabolic relevance, 4) the potential roles of BAT in health and diseases, and 5) the avenues for therapeutic targeting of BAT in obesity. These questions will be discussed on the background of known biology of BAT in rodents. II. A Historical Perspective Understanding the biology of a body organ requires knowledge of location, morphology, regulation, and function. In contrast to other classic metabolic organs, such as skeletal muscle, WAT, and liver, the biology of BAT in humans has remained elusive since Gessner first described its presence in hibernators in 1551. The 1960s heralded a golden era of human BAT research that withered in the late 1980s with the view that significant deposits of BAT did not persist beyond childhood. In the last decade, unequivocal evidence of BAT in adult humans has led to resurgence in global research interest. Table 1 summarizes major developments in human BAT research. Endocrine Reviews, June 2013, 34(3):413– 438 At the beginning of the last century, anatomists described similarities between fat masses located in the dorsal and cervical region of human fetuses and fat depots in the interscapular area of hibernating mammals (10 –12). It was, however, not until the 1960s that BAT was ascribed a regulatory role in thermogenenesis (13–18). It was proposed that BAT was a heat-producing tissue in small mammals and human infants, defending newborns from hypothermia. BAT is histologically and functionally distinct from WAT, and the presence of the facultative proton transporter UCP1 confers upon it the unique ability to generate heat through respiratory uncoupling (19). The thermogenic properties of BAT originally were of interest only to a few scientists studying hibernating animals. Serial publications revealed a 6-fold increase in heat production from BAT after cold acclimatization in rodents, dissipating heat to the body via dense vascularization juxtaposing deep viscera (13, 20 –22). The striking thermogenic capacity of BAT led some researchers to regard it as an electric blanket for animals in the cold (23). Because temperature changes are cues to food availability in nature, BAT studies were extended to investigating response to nutrient variations. In the 1970s, Rothwell and Table 1. Timeline and Summary of Major Developments in Human BAT Research Year Authors 1902 Hatai 1908 1922 1964 Bonnot Rasmussen Silverman et al 1965 Dawkins and Scopes 1972 Heaton 1983 19 (...truncated)