Brown and beige fat in humans: Thermogenic adipocytes that control energy and glucose homeostasis

Journal of Clinical Investigation

Volumn 125, Issue 2, 2015, Pages 478-486

  Sidossis, Labros ^a   Kajimura, Shingo ^b  

^a UNIVERSITY OF TEXAS MEDICAL BRANCH   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADIPOCYTE; ADIPOSE TISSUE; BEIGE ADIPOCYTE; BEIGE FAT; BROWN ADIPOCYTE; BROWN ADIPOSE TISSUE; CACHEXIA; CELL MATURATION; ENERGY BALANCE; ENERGY METABOLISM; ENVIRONMENTAL ENRICHMENT; GLUCOSE HOMEOSTASIS; HUMAN; OBESITY; PRIORITY JOURNAL; REVIEW; THERMOGENESIS; WHITE ADIPOCYTE; WHITE ADIPOSE TISSUE; ADULT; ANIMAL; METABOLISM; NON INSULIN DEPENDENT DIABETES MELLITUS; PATHOLOGY; PHYSIOLOGY;

GLUCOSE;

ADIPOSE TISSUE, BROWN; ADULT; ANIMALS; DIABETES MELLITUS, TYPE 2; ENERGY METABOLISM; GLUCOSE; HUMANS; OBESITY; THERMOGENESIS;

EID: 84961290714     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI78362     Document Type: Review

References (117)

1. Cunningham DJ, Stolwijk JA, Wenger CB. Comparative thermoregulatory responses of resting men and women. J Appl Physiol. 1978;45(6):908-915.
2. Lean ME. Brown adipose tissue in humans. Proc Nutr Soc. 1989;48(2):243-256.
3. Bonnot E. The interscapular gland. J Anat Physiol. 1908;43(pt 1):43-58.
4. Rasmussen A. The glandular status of brown multilocular adipose tissue. Endocrinology. 1922;6(6):760-770.
5. Huttunen P, Kortelainen ML. Long-term alcohol consumption and brown adipose tissue in man. Eur J Appl Physiol Occup Physiol. 1990;60(6):418-424.
6. Huttunen P, Hirvonen J, Kinnula V. The occurrence of brown adipose tissue in outdoor workers. Eur J Appl Physiol Occup Physiol. 1981;46(4):339-345.
7. Heaton JM. The distribution of brown adipose tissue in the human. J Anat. 1972;112(pt 1):35-39.
8. Astrup A, Bulow J, Christensen NJ, Madsen J. Ephedrine-induced thermogenesis in man: no role for interscapular brown adipose tissue. Clin Sci (Lond). 1984;66(2):179-186.
9. Hany TF, Gharehpapagh E, Kamel EM, Buck A, Himms-Hagen J, von Schulthess GK. Brown adipose tissue: a factor to consider in symmetrical tracer uptake in the neck and upper chest region. Eur J Nucl Med Mol Imaging. 2002;29(10):1393-1398.
10. Yeung HW, Grewal RK, Gonen M, Schoder H, Larson SM. Patterns of (18) F-FDG uptake in adipose tissue and muscle: a potential source of false-positives for PET. J Nucl Med. 2003;44(11):1789-1796.
11. Truong MT, et al. Focal FDG uptake in mediastinal brown fat mimicking malignancy: a potential pitfall resolved on PET/CT. AJR Am J Roentgenol. 2004;183(4):1127-1132.
12. Soderlund V, Larsson SA, Jacobsson H. Reduction of FDG uptake in brown adipose tissue in clinical patients by a single dose of propranolol. Eur J Nucl Med Mol Imaging. 2007;34(7):1018-1022.
13. Christensen CR, Clark PB, Morton KA. Reversal of hypermetabolic brown adipose tissue in F-18 FDG PET imaging. Clin Nucl Med. 2006;31(4):193-196.
14. Garcia CA, et al. Reduction of brown fat 2-deoxy-2-[F-18]fluoro-D-glucose uptake by controlling environmental temperature prior to positron emission tomography scan. Mol Imaging Biol. 2006;8(1):24-29.
15. van Marken Lichtenbelt WD, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med. 2009;360(15):1500-1508.
16. Cypess AM, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med. 2009;360(15):1509-1517.
17. Virtanen KA, et al. Functional brown adipose tissue in healthy adults. N Engl J Med. 2009;360(15):1518-1525.
18. Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab. 2007;293(2):E444-E452.
19. Saito M, et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes. 2009;58(7):1526-1531.
20. Chondronikola M, et al. Brown adipose tissue improves whole body glucose homeostasis and insulin sensitivity in humans. Diabetes. 2014;63(12):4089-4099.
21. Orava J, et al. Blunted metabolic responses to cold and insulin stimulation in brown adipose tissue of obese humans. Obesity (Silver Spring). 2013;21(11):2279-2287.
22. Kajimura S, Saito M. A new era in brown adipose tissue biology: molecular control of brown fat development and energy homeostasis. Annu Rev Physiol. 2014;76:225-249.
23. Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med. 2013;19(10):1252-1263.
24. Wu J, Cohen P, Spiegelman BM. Adaptive thermogenesis in adipocytes: is beige the new brown? Genes Dev. 2013;27(3):234-250.
25. Shabalina IG, Petrovic N, de Jong JM, Kalinovich AV, Cannon B, Nedergaard J. UCP1 in brite/beige adipose tissue mitochondria is functionally thermogenic. Cell Rep. 2013;5(5):1196-1203.
26. Wu J, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 2012;150(2):366-376.
27. Lidell ME, et al. Evidence for two types of brown adipose tissue in humans. Nat Med. 2013;19(5):631-634.
28. Cinti S. The Adipose Organ. Milano, Italy: Editrice Kurtis; 1999.
29. Murano I, Barbatelli G, Giordano A, Cinti S. Noradrenergic parenchymal nerve fiber branching after cold acclimatisation correlates with brown adipocyte density in mouse adipose organ. J Anat. 2009;214(1):171-178.
30. Zingaretti MC, et al. The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J. 2009;23(9):3113-3120.
31. Atit R, et al. Beta-catenin activation is necessary and sufficient to specify the dorsal dermal fate in the mouse. Dev Biol. 2006;296(1):164-176.
32. Seale P, et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature. 2008;454(7207):961-967.
33. Lepper C, Fan CM. Inducible lineage tracing of Pax7-descendant cells reveals embryonic origin of adult satellite cells. Genesis. 2010;48(7):424-436.
34. Walden TB, Timmons JA, Keller P, Nedergaard J, Cannon B. Distinct expression of muscle-specific microRNAs (myomirs) in brown adipocytes. J Cell Physiol. 2009;218(2):444-449.
35. Timmons JA, et al. Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages. Proc Natl Acad Sci U S A. 2007;104(11):4401-4406.
36. Forner F, Kumar C, Luber CA, Fromme T, Klingenspor M, Mann M. Proteome differences between brown and white fat mitochondria reveal specialized metabolic functions. Cell Metab. 2009;10(4):324-335.
37. Lee YH, Petkova AP, Mottillo EP, Granneman JG. In vivo identification of bipotential adipocyte progenitors recruited by beta3-adrenoceptor activation and high-fat feeding. Cell Metab. 2012;15(4):480-491.
38. Sanchez-Gurmaches J, Hung CM, Sparks CA, Tang Y, Li H, Guertin DA. PTEN loss in the Myf5 lineage redistributes body fat and reveals subsets of white adipocytes that arise from Myf5 precursors. Cell Metab. 2012;16(3):348-362.
39. Long JZ, et al. A smooth muscle-like origin for beige adipocytes. Cell Metab. 2014;19(5):810-820.
40. Barbatelli G, et al. The emergence of cold-induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation. Am J Physiol Endocrinol Metab. 2010;298(6):E1244-E1253.
41. Himms-Hagen J, Melnyk A, Zingaretti MC, Ceresi E, Barbatelli G. Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes. Am J Physiol Cell Physiol. 2000;279(3):C670-C681.
42. Frontini A, et al. White-to-brown transdifferentiation of omental adipocytes in patients affected by pheochromocytoma. Biochim Biophys Acta. 2013;1831(5):950-959.
43. Rosenwald M, Perdikari A, Rulicke T, Wolfrum C. Bi-directional interconversion of brite and white adipocytes. Nat Cell Biol. 2013;15(6):659-667.
44. Wang QA, Tao C, Gupta RK, Scherer PE. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat Med. 2013;19(10):1338-1344.
45. Sharp LZ, et al. Human BAT possesses molecular signatures that resemble beige/brite cells. PLoS One. 2012;7(11):e49452.
46. Petrovic N, Walden TB, Shabalina IG, Timmons JA, Cannon B, Nedergaard J. Chronic peroxisome proliferator-activated receptor gamma (PPARβ) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. J Biol Chem. 2009;285(10):7153-7164.
47. Jespersen NZ, et al. A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans. Cell Metab. 2013;17(5):798-805.
48. Cypess AM, et al. Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat Med. 2013;19(5):635-639.
49. Yoneshiro T, et al. Recruited brown adipose tissue as an antiobesity agent in humans. J Clin Invest. 2013;123(8):3404-3408.
50. van der Lans AA, et al. Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. J Clin Invest. 2013;123(8):3395-3403.
51. Lee P, et al. Temperature-acclimated brown adipose tissue modulates insulin sensitivity in humans. Diabetes. 2014;63(11):3686-3698.
52. Kajimura S, Seale P, Spiegelman BM. Transcriptional control of brown fat development. Cell Metab. 2010;11(4):257-262.
53. Collins S. β-Adrenoceptor signaling networks in adipocytes for recruiting stored fat and energy expenditure. Front Endocrinol (Lausanne). 2011;2:102.
54. Nguyen KD, et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature. 2011;480(7375):104-108.
55. Qiu Y, et al. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell. 2014;157(6):1292-1308.
56. Cao L, et al. White to brown fat phenotypic switch induced by genetic and environmental activation of a hypothalamic-adipocyte axis. Cell Metab. 2011;14(3):324-338.
57. Bostrom P, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481(7382):463-468.
58. Xu X, et al. Exercise ameliorates high-fat dietinduced metabolic and vascular dysfunction, and increases adipocyte progenitor cell population in brown adipose tissue. Am J Physiol Regul Integr Comp Physiol. 2011;300(5):R1115-R1125.
59. Finck BN, Kelly DP. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J Clin Invest. 2006;116(3):615-622.
60. Rao RR, et al. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell. 2014;157(6):1279-1291.
61. Lee P, et al. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab. 2014;19(2):302-309.
62. Knudsen JG, et al. Role of IL-6 in exercise training- and cold-induced UCP1 expression in subcutaneous white adipose tissue. PLoS One. 2014;9(1):e84910.
63. Carriere A, et al. Browning of white adipose cells by intermediate metabolites: an adaptive mechanism to alleviate redox pressure. Diabetes. 2014;63(10):3253-3265.
64. Petruzzelli M, et al. A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metab. 2014;20(3):433-447.
65. Kir S, et al. Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature. 2014;513(7516):100-104.
66. Qian SW, et al. BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis. Proc Natl Acad Sci U S A. 2013;110(9):E798-E807.
67. Schulz TJ, et al. Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat. Proc Natl Acad Sci U S A. 2011;108(1):143-148.
68. Tseng YH, et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature. 2008;454(7207):1000-1004.
69. Whittle AJ, et al. BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell. 2012;149(4):871-885.
70. Tomlinson E, et al. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology. 2002;143(5):1741-1747.
71. Fu L, et al. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology. 2004;145(6):2594-2603.
72. Fisher FM, et al. FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 2012;26(3):271-281.
73. Emanuelli B, et al. Interplay between FGF21 and insulin action in the liver regulates metabolism. J Clin Invest. 2014;124(2):515-527.
74. Hinoi E, et al. Growth differentiation factor-5 promotes brown adipogenesis in systemic energy expenditure. Diabetes. 2014;63(1):162-175.
75. Bordicchia M, et al. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J Clin Invest. 2012;122(3):1022-1036.
76. Madsen L, et al. UCP1 induction during recruitment of brown adipocytes in white adipose tissue is dependent on cyclooxygenase activity. PLoS One. 2010;5(6):e11391.
77. Vegiopoulos A, et al. Cyclooxygenase-2 controls energy homeostasis in mice by de novo recruitment of brown adipocytes. Science. 2010;328(5982):1158-1161.
78. Sun K, et al. Dichotomous effects of VEGF-A on adipose tissue dysfunction. Proc Natl Acad Sci U S A. 2012;109(15):5874-5879.
79. Elias I, et al. Adipose tissue overexpression of vascular endothelial growth factor protects against diet-induced obesity and insulin resistance. Diabetes. 2012;61(7):1801-1813.
80. Roberts LD, et al. beta-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metab. 2014;19(1):96-108.
81. Yadav H, et al. Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling. Cell Metab. 2011;14(1):67-79.
82. Koncarevic A, et al. A novel therapeutic approach to treating obesity through modulation of TGFβ signaling. Endocrinology. 2012;153(7):3133-3146.
83. Fournier B, et al. Blockade of the activin receptor IIb activates functional brown adipogenesis and thermogenesis by inducing mitochondrial oxidative metabolism. Mol Cell Biol. 2012;32(14):2871-2879.
84. Kiefer FW, et al. Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue. Nat Med. 2012;18(6):918-925.
85. Bi P, et al. Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity. Nat Med. 2014;20(8):911-918.
86. Kajimura S, et al. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-β transcriptional complex. Nature. 2009;460(7259):1154-1158.
87. Kajimura S, et al. Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex. Genes Dev. 2008;22(10):1397-1409.
88. Ohno H, Shinoda K, Ohyama K, Sharp LZ, Kajimura S. EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex. Nature. 2013;504(7478):163-167.
89. Harms MJ, et al. Prdm16 is required for the maintenance of brown adipocyte identity and function in adult mice. Cell Metab. 2014;19(4):593-604.
90. Rajakumari S, et al. EBF2 determines and maintains brown adipocyte identity. Cell Metab. 2013;17(4):562-574.
91. Ohno H, Shinoda K, Spiegelman BM, Kajimura S. PPARγ agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metab. 2012;15(3):395-404.
92. Cohen P, et al. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell. 2014;156(1):304-316.
93. Kozak LP. The genetics of brown adipocyte induction in white fat depots. Front Endocrinol (Lausanne). 2011;2:64.
94. Xue B, Rim JS, Hogan JC, Coulter AA, Koza RA, Kozak LP. Genetic variability affects the development of brown adipocytes in white fat but not in interscapular brown fat. J Lipid Res. 2007;48(1):41-51.
95. Xue B, Coulter A, Rim JS, Koza RA, Kozak LP. Transcriptional synergy and the regulation of Ucp1 during brown adipocyte induction in white fat depots. Mol Cell Biol. 2005;25(18):8311-8322.
96. Valve R, Heikkinen S, Rissanen A, Laakso M, Uusitupa M. Synergistic effect of polymorphisms in uncoupling protein 1 and beta3-adrenergic receptor genes on basal metabolic rate in obese Finns. Diabetologia. 1998;41(3):357-361.
97. Nagai N, Sakane N, Tsuzaki K, Moritani T. UCP1 genetic polymorphism (-3826 A/G) diminishes resting energy expenditure and thermoregulatory sympathetic nervous system activity in young females. Int J Obes (Lond). 2011;35(8):1050-1055.
98. Yoneshiro T, et al. Impact of UCP1 and beta3AR gene polymorphisms on age-related changes in brown adipose tissue and adiposity in humans. Int J Obes (Lond). 2013;37(7):993-998.
99. Cormier-Daire V, et al. Cryptic terminal deletion of chromosome 9q34: a novel cause of syndromic obesity in childhood? J Med Genet. 2003;40(4):300-303.
100. Willemsen MH, et al. Update on Kleefstra syndrome. Mol Syndromol. 2012;2(3):202-212.
101. Wang J, et al. Ablation of LGR4 promotes energy expenditure by driving white-to-brown fat switch. Nat Cell Biol. 2013;15(12):1455-1463.
102. Feldmann HM, Golozoubova V, Cannon B, Nedergaard J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab. 2009;9(2):203-209.
103. Stanford KI, et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest. 2013;123(1):215-223.
104. Bartelt A, et al. Brown adipose tissue activity controls triglyceride clearance. Nat Med. 2011;17(2):200-205.
105. Seale P, et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest. 2011;121(1):96-105.
106. Pfannenberg C, et al. Impact of age on the relationships of brown adipose tissue with sex and adiposity in humans. Diabetes. 2010;59(7):1789-1793.
107. Lee P, Greenfield JR, Ho KK, Fulham MJ. A critical appraisal of the prevalence and metabolic significance of brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab. 2010;299(4):E601-E606.
108. Jacene HA, Cohade CC, Zhang Z, Wahl RL. The relationship between patients' serum glucose levels and metabolically active brown adipose tissue detected by PET/CT. Mol Imaging Biol. 2011;13(6):1278-1283.
109. Ouellet V, et al. Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans. J Clin Endocrinol Metab. 2011;96(1):192-199.
110. Orava J, et al. Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metab. 2011;14(2):272-279.
111. Chen KY, et al. Brown fat activation mediates cold-induced thermogenesis in adult humans in response to a mild decrease in ambient temperature. J Clin Endocrinol Metab. 2013;98(7):E1218-E1223.
112. Yoneshiro T, et al. Brown adipose tissue, wholebody energy expenditure, and thermogenesis in healthy adult men. Obesity. 2011;19(1):13-16.
113. Ouellet V, et al. Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J Clin Invest. 2012;122(2):545-552.
114. Matsushita M, Yoneshiro T, Aita S, Kameya T, Sugie H, Saito M. Impact of brown adipose tissue on body fatness and glucose metabolism in healthy humans. Int J Obes (Lond). 2014;38(6):812-817.
115. Cypess AM, Haft CR, Laughlin MR, Hu HH. Brown fat in humans: consensus points and experimental guidelines. Cell Metab. 2014;20(3):408-415.
116. Carey AL, et al. Ephedrine activates brown adipose tissue in lean but not obese humans. Diabetologia. 2013;56(1):147-155.
117. Galmozzi A, et al. ThermoMouse: An in vivo model to identify modulators of UCP1 expression in brown adipose tissue. Cell Report. 2014;9(5):1-10.