Brown and beige fat: the metabolic function, induction, and therapeutic potential

Abstract

Adipose tissue is an important organ for energy homeostasis. White adipose tissue stores energy in the form of triglycerides, whereas brown adipocytes and recently identified beige adipocytes are specialized in dissipating energy by thermogenesis or contribution to dispose glucose and clear triglycerides in blood. The inverse correlation between the brown adipose tissue activity and body mass suggests its protective role against body fat accumulation. Thus, recruitment and activation of brown or beige adipose tissue become particularly appealing targets for increasing energy expenditure. Angiogenesis and sympathetic nerve signals are the fundamental determinants for brown and beige adipose tissue development, as well as for their metabolic functions. Secretary factors including BMPs can induce the development, the activation of brown or beige adipose tissue, which seem to be promising for therapeutic development.

Keywords

brown adipocyte / beige adipocyte / metabolism / obesity

References

[1] Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, Mullany EC, Biryukov S, Abbafati C, Abera SF, Abraham JP, Abu-Rmeileh NM, Achoki T, AlBuhairan FS, Alemu ZA, Alfonso R, Ali MK, Ali R, Guzman NA, Ammar W, Anwari P, Banerjee A, Barquera S, Basu S, Bennett DA, Bhutta Z, Blore J, Cabral N, Nonato IC, Chang JC, Chowdhury R, Courville KJ, Criqui MH, Cundiff DK, Dabhadkar KC, Dandona L, Davis A, Dayama A, Dharmaratne SD, Ding EL, Durrani AM, Esteghamati A, Farzadfar F, Fay DF, Feigin VL, Flaxman A, Forouzanfar MH, Goto A, Green MA, Gupta R, Hafezi-Nejad N, Hankey GJ, Harewood HC, Havmoeller R, Hay S, Hernandez L, Husseini A, Idrisov BT, Ikeda N, Islami F, Jahangir E, Jassal SK, Jee SH, Jeffreys M, Jonas JB, Kabagambe EK, Khalifa SE, Kengne AP, Khader YS, Khang YH, Kim D, Kimokoti RW, Kinge JM, Kokubo Y, Kosen S, Kwan G, Lai T, Leinsalu M, Li Y, Liang X, Liu S, Logroscino G, Lotufo PA, Lu Y, Ma J, Mainoo NK, Mensah GA, Merriman TR, Mokdad AH, Moschandreas J, Naghavi M, Naheed A, Nand D, Narayan KM, Nelson EL, Neuhouser ML, Nisar MI, Ohkubo T, Oti SO, Pedroza A, Prabhakaran D, Roy N, Sampson U, Seo H, Sepanlou SG, Shibuya K, Shiri R, Shiue I, Singh GM, Singh JA, Skirbekk V, Stapelberg NJ, Sturua L, Sykes BL, Tobias M, Tran BX, Trasande L, Toyoshima H, van de Vijver S, Vasankari TJ, Veerman JL, Velasquez-Melendez G, Vlassov VV, Vollset SE, Vos T, Wang C, Wang X, Weiderpass E, Werdecker A, Wright JL, Yang YC, Yatsuya H, Yoon J, Yoon SJ, Zhao Y, Zhou M, Zhu S, Lopez AD, Murray CJ, Gakidou E. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet2014; 384(9945): 766–781

[2] Bornfeldt KE, Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab2011; 14(5): 575–585

[3] Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, Ford E, Furie K, Go A, Greenlund K, Haase N, Hailpern S, Ho M, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott M, Meigs J, Mozaffarian D, Nichol G, O’Donnell C, Roger V, Rosamond W, Sacco R, Sorlie P, Stafford R, Steinberger J, Thom T, Wasserthiel-Smoller S, Wong N, Wylie-Rosett J, Hong Y; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation2009; 119(3): 480–486

[4] Gesta S, Tseng YH, Kahn CR. Developmental origin of fat: tracking obesity to its source. Cell2007; 131(2): 242–256

[5] Virtanen KA, Nuutila P. Brown adipose tissue in humans. Curr Opin Lipidol2011; 22(1): 49–54

[6] Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature2006; 444(7121): 847–853

[7] Cannon B, Houstek J, Nedergaard J. Brown adipose tissue. More than an effector of thermogenesis? Ann N Y Acad Sci1998; 856(1 MOLECULAR MEC): 171–187

[8] Villarroya J, Cereijo R, Villarroya F. An endocrine role for brown adipose tissue? Am J Physiol Endocrinol Metab2013; 305(5): E567–E572

[9] Young P, Arch JR, Ashwell M. Brown adipose tissue in the parametrial fat pad of the mouse. FEBS Lett 1984; 167(1): 10–14

[10] Loncar D, Afzelius BA, Cannon B. Epididymal white adipose tissue after cold stress in rats. I. Nonmitochondrial changes. J Ultrastruct Mol Struct Res1988; 101(2–3): 109–122

[11] Loncar D, Afzelius BA, Cannon B. Epididymal white adipose tissue after cold stress in rats. II. Mitochondrial changes. J Ultrastruct Mol Struct Res1988; 101(2–3): 199–209

[12] Loncar D, Bedrica L, Mayer J, Cannon B, Nedergaard J, Afzelius BA, Svajger A. The effect of intermittent cold treatment on the adipose tissue of the cat. Apparent transformation from white to brown adipose tissue. J Ultrastruct Mol Struct Res1986; 97(1–3): 119–129

[13] Almind K, Manieri M, Sivitz WI, Cinti S, Kahn CR. Ectopic brown adipose tissue in muscle provides a mechanism for differences in risk of metabolic syndrome in mice. Proc Natl Acad Sci USA2007; 104(7): 2366–2371

[14] 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 Res2007; 48(1): 41–51

[15] Guerra C, Koza RA, Yamashita H, Walsh K, Kozak LP. Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity. J Clin Invest1998; 102(2): 412–420

[16] Cousin B, Cinti S, Morroni M, Raimbault S, Ricquier D, Pénicaud L, Casteilla L. Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization. J Cell Sci1992; 103(Pt 4): 931–942

[17] Himms-Hagen J, Melnyk A, Zingaretti MC, Ceresi E, Barbatelli G, Cinti S. Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes. Am J Physiol Cell Physiol2000; 279(3): C670–C681

[18] Picó C, Bonet ML, Palou A. Stimulation of uncoupling protein synthesis in white adipose tissue of mice treated with the beta 3-adrenergic agonist CGP-12177. Cell Mol Life Sci1998; 54(2): 191–195

[19] Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab2007; 293(2): E444–E452

[20] Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng YH, Doria A, Kolodny GM, Kahn CR. Identification and importance of brown adipose tissue in adult humans. N Engl J Med2009; 360(15): 1509–1517

[21] Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J, Iwanaga T, Miyagawa M, Kameya T, Nakada K, Kawai Y, Tsujisaki M. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes2009; 58(7): 1526–1531

[22] van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJ. Cold-activated brown adipose tissue in healthy men. N Engl J Med2009; 360(15): 1500–1508

[23] Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ, Enerbäck S, Nuutila P. Functional brown adipose tissue in healthy adults. N Engl J Med2009; 360(15): 1518–1525

[24] Zingaretti MC, Crosta F, Vitali A, Guerrieri M, Frontini A, Cannon B, Nedergaard J, Cinti S. The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J2009; 23(9): 3113–3120

[25] Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV, Gygi SP, Spiegelman BM. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature2009; 460(7259): 1154–1158

[26] Timmons JA, Wennmalm K, Larsson O, Walden TB, Lassmann T, Petrovic N, Hamilton DL, Gimeno RE, Wahlestedt C, Baar K, Nedergaard J, Cannon B. Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages. Proc Natl Acad Sci USA2007; 104(11): 4401–4406

[27] Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, Scimè A, Devarakonda S, Conroe HM, Erdjument-Bromage H, Tempst P, Rudnicki MA, Beier DR, Spiegelman BM. PRDM16 controls a brown fat/skeletal muscle switch. Nature2008; 454(7207): 961–967

[28] Wu J, Boström P, Sparks LM, Ye L, Choi JH, Giang AH, Khandekar M, Virtanen KA, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt WD, Hoeks J, Enerbäck S, Schrauwen P, Spiegelman BM. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell2012; 150(2): 366–376

[29] Waldén TB, Hansen IR, Timmons JA, Cannon B, Nedergaard J. Recruited vs. nonrecruited molecular signatures of brown, “brite,” and white adipose tissues. Am J Physiol Endocrinol Metab2012; 302(1): E19–E31

[30] Sharp LZ, Shinoda K, Ohno H, Scheel DW, Tomoda E, Ruiz L, Hu H, Wang L, Pavlova Z, Gilsanz V, Kajimura S. Human BAT possesses molecular signatures that resemble beige/brite cells. PLoS ONE2012; 7(11): e49452

[31] Lidell ME, Betz MJ, Dahlqvist Leinhard O, Heglind M, Elander L, Slawik M, Mussack T, Nilsson D, Romu T, Nuutila P, Virtanen KA, Beuschlein F, Persson A, Borga M, Enerbäck S. Evidence for two types of brown adipose tissue in humans. Nat Med2013; 19(5): 631–634

[32] Lidell ME, Betz MJ, Enerbäck S. Two types of brown adipose tissue in humans. Adipocyte2014; 3(1): 63–66

[33] Cypess AM, White AP, Vernochet C, Schulz TJ, Xue R, Sass CA, Huang TL, Roberts-Toler C, Weiner LS, Sze C, Chacko AT, Deschamps LN, Herder LM, Truchan N, Glasgow AL, Holman AR, Gavrila A, Hasselgren PO, Mori MA, Molla M, Tseng YH. Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat Med2013; 19(5): 635–639

[34] Jespersen NZ, Larsen TJ, Peijs L, Daugaard S, Homøe P, Loft A, de Jong J, Mathur N, Cannon B, Nedergaard J, Pedersen BK, Møller K, Scheele C. A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans. Cell Metab2013; 17(5): 798–805

[35] Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev2004; 84(1): 277–359

[36] Foster DO, Frydman ML. Tissue distribution of cold-induced thermogenesis in conscious warm- or cold-acclimated rats reevaluated from changes in tissue blood flow: the dominant role of brown adipose tissue in the replacement of shivering by nonshivering thermogenesis. Can J Physiol Pharmacol1979; 57(3): 257–270

[37] Rothwell NJ, Stock MJ. Luxuskonsumption, diet-induced thermogenesis and brown fat: the case in favour. Clin Sci (Lond)1983; 64(1): 19–23

[38] Ghorbani M, Claus TH, Himms-Hagen J. Hypertrophy of brown adipocytes in brown and white adipose tissues and reversal of diet-induced obesity in rats treated with a beta3-adrenoceptor agonist. Biochem Pharmacol1997; 54(1): 121–131

[39] Lowell BB, S-Susulic V, Hamann A, Lawitts JA, Himms-Hagen J, Boyer BB, Kozak LP, Flier JS. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature1993; 366(6457): 740–742

[41] Nikami H, Shimizu Y, Endoh D, Yano H, Saito M. Cold exposure increases glucose utilization and glucose transporter expression in brown adipose tissue. Biochem Biophys Res Commun1992; 185(3): 1078–1082

[42] Dallner OS, Chernogubova E, Brolinson KA, Bengtsson T. Beta3-adrenergic receptors stimulate glucose uptake in brown adipocytes by two mechanisms independently of glucose transporter 4 translocation. Endocrinology2006; 147(12): 5730–5739

[43] Stanford KI, Middelbeek RJ, Townsend KL, An D, Nygaard EB, Hitchcox KM, Markan KR, Nakano K, Hirshman MF, Tseng YH, Goodyear LJ. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest2013; 123(1): 215–223

[40] Ouellet V, Routhier-Labadie A, Bellemare W, Lakhal-Chaieb L, Turcotte E, Carpentier AC, Richard D. 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 Metab2011; 96(1): 192–199

[44] Crandall DL, Hausman GJ, Kral JG. A review of the microcirculation of adipose tissue: anatomic, metabolic, and angiogenic perspectives. Microcirculation1997; 4(2): 211–232

[45] Jansson PA. Endothelial dysfunction in insulin resistance and type 2 diabetes. J Intern Med2007; 262(2): 173–183

[46] Sierra-Honigmann MR, Nath AK, Murakami C, García-Cardeña G, Papapetropoulos A, Sessa WC, Madge LA, Schechner JS, Schwabb MB, Polverini PJ, Flores-Riveros JR. Biological action of leptin as an angiogenic factor. Science1998; 281(5383): 1683–1686

[47] Cao Y. Angiogenesis modulates adipogenesis and obesity. J Clin Invest2007; 117(9): 2362–2368

[48] Voros G, Maquoi E, Demeulemeester D, Clerx N, Collen D, Lijnen HR. Modulation of angiogenesis during adipose tissue development in murine models of obesity. Endocrinology2005; 146(10): 4545–4554

[49] Wang Y, Lam JB, Lam KS, Liu J, Lam MC, Hoo RL, Wu D, Cooper GJ, Xu A. Adiponectin modulates the glycogen synthase kinase-3beta/beta-catenin signaling pathway and attenuates mammary tumorigenesis of MDA-MB-231 cells in nude mice. Cancer Res2006; 66(23): 11462–11470

[50] Bråkenhielm E, Veitonmäki N, Cao R, Kihara S, Matsuzawa Y, Zhivotovsky B, Funahashi T, Cao Y. Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci USA2004; 101(8): 2476–2481

[51] Cao R, Brakenhielm E, Wahlestedt C, Thyberg J, Cao Y. Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF. Proc Natl Acad Sci USA2001; 98(11): 6390–6395

[52] Hausman GJ, Richardson RL. Adipose tissue angiogenesis. J Anim Sci2004; 82(3): 925–934

[53] Zhang QX, Magovern CJ, Mack CA, Budenbender KT, Ko W, Rosengart TK. Vascular endothelial growth factor is the major angiogenic factor in omentum: mechanism of the omentum-mediated angiogenesis. J Surg Res1997; 67(2): 147–154

[54] Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J1999; 13(1): 9–22

[55] Elias I, Franckhauser S, Ferré T, Vilà L, Tafuro S, Muñoz S, Roca C, Ramos D, Pujol A, Riu E, Ruberte J, Bosch F. Adipose tissue overexpression of vascular endothelial growth factor protects against diet-induced obesity and insulin resistance. Diabetes2012; 61(7): 1801–1813

[56] Sung HK, Doh KO, Son JE, Park JG, Bae Y, Choi S, Nelson SM, Cowling R, Nagy K, Michael IP, Koh GY, Adamson SL, Pawson T, Nagy A. Adipose vascular endothelial growth factor regulates metabolic homeostasis through angiogenesis. Cell Metab2013; 17(1): 61–72

[57] Sun K, Wernstedt Asterholm I, Kusminski CM, Bueno AC, Wang ZV, Pollard JW, Brekken RA, Scherer PE. Dichotomous effects of VEGF-A on adipose tissue dysfunction. Proc Natl Acad Sci USA2012; 109(15): 5874–5879

[58] Shimizu I, Aprahamian T, Kikuchi R, Shimizu A, Papanicolaou KN, MacLauchlan S, Maruyama S, Walsh K. Vascular rarefaction mediates whitening of brown fat in obesity. J Clin Invest2014; 124(5): 2099–2112

[59] Xue Y, Petrovic N, Cao R, Larsson O, Lim S, Chen S, Feldmann HM, Liang Z, Zhu Z, Nedergaard J, Cannon B, Cao Y. Hypoxia-independent angiogenesis in adipose tissues during cold acclimation. Cell Metab2009; 9(1): 99–109

[60] Crossno JT Jr, Majka SM, Grazia T, Gill RG, Klemm DJ. Rosiglitazone promotes development of a novel adipocyte population from bone marrow-derived circulating progenitor cells. J Clin Invest2006; 116(12): 3220–3228

[61] Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, Andriolo G, Sun B, Zheng B, Zhang L, Norotte C, Teng PN, Traas J, Schugar R, Deasy BM, Badylak S, Buhring HJ, Giacobino JP, Lazzari L, Huard J, Péault B. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell2008; 3(3): 301–313

[62] Traktuev DO, Merfeld-Clauss S, Li J, Kolonin M, Arap W, Pasqualini R, Johnstone BH, March KL. A population of multipotent CD34-positive adipose stromal cells share pericyte and mesenchymal surface markers, reside in a periendothelial location, and stabilize endothelial networks. Circ Res2008; 102(1): 77–85

[63] Tran KV, Gealekman O, Frontini A, Zingaretti MC, Morroni M, Giordano A, Smorlesi A, Perugini J, De Matteis R, Sbarbati A, Corvera S, Cinti S. The vascular endothelium of the adipose tissue gives rise to both white and brown fat cells. Cell Metab2012; 15(2): 222–229

[64] Tang W, Zeve D, Suh JM, Bosnakovski D, Kyba M, Hammer RE, Tallquist MD, Graff JM. White fat progenitor cells reside in the adipose vasculature. Science2008; 322(5901): 583–586

[65] da Silva Meirelles L, Caplan AI, Nardi NB. In search of the in vivo identity of mesenchymal stem cells. Stem Cells 2008; 26(9): 2287–2299

[66] Wang QA, Tao C, Gupta RK, Scherer PE. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat Med2013; 19(10): 1338–1344

[67] Nguyen KD, Qiu Y, Cui X, Goh YP, Mwangi J, David T, Mukundan L, Brombacher F, Locksley RM, Chawla A. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature2011; 480(7375): 104–108

[68] Qiu Y, Nguyen KD, Odegaard JI, Cui X, Tian X, Locksley RM, Palmiter RD, Chawla A. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell2014; 157(6): 1292–1308

[69] Nicholls DG. The physiological regulation of uncoupling proteins. Biochim Biophys Acta2006; 1757(5–6): 459–466

[70] Fedorenko A, Lishko PV, Kirichok Y. Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell2012; 151(2): 400–413

[71] Robidoux J, Cao W, Quan H, Daniel KW, Moukdar F, Bai X, Floering LM, Collins S. Selective activation of mitogen-activated protein (MAP) kinase kinase 3 and p38alpha MAP kinase is essential for cyclic AMP-dependent UCP1 expression in adipocytes. Mol Cell Biol2005; 25(13): 5466–5479

[72] Bonet ML, Oliver P, Palou A. Pharmacological and nutritional agents promoting browning of white adipose tissue. Biochim Biophys Acta2013; 1831(5): 969–985

[73] Cao W, Daniel KW, Robidoux J, Puigserver P, Medvedev AV, Bai X, Floering LM, Spiegelman BM, Collins S. p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene. Mol Cell Biol2004; 24(7): 3057–3067

[74] Bukowiecki L, Collet AJ, Follea N, Guay G, Jahjah L. Brown adipose tissue hyperplasia: a fundamental mechanism of adaptation to cold and hyperphagia. Am J Physiol1982; 242(6): E353–E359

[75] Desautels M, Dulos RA, Mozaffari B. Selective loss of uncoupling protein from mitochondria of surgically denervated brown adipose tissue of cold-acclimated mice. Biochem Cell Biol1986; 64(11): 1125–1134

[76] 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 Anat2009; 214(1): 171–178

[77] Jimenez M, Barbatelli G, Allevi R, Cinti S, Seydoux J, Giacobino JP, Muzzin P, Preitner F. Beta 3-adrenoceptor knockout in C57BL/6J mice depresses the occurrence of brown adipocytes in white fat. Eur J Biochem2003; 270(4): 699–705

[78] Mori M, Nakagami H, Rodriguez-Araujo G, Nimura K, Kaneda Y. Essential role for miR-196a in brown adipogenesis of white fat progenitor cells. PLoS Biol2012; 10(4): e1001314

[79] Kim YJ, Bae SW, Yu SS, Bae YC, Jung JS. miR-196a regulates proliferation and osteogenic differentiation in mesenchymal stem cells derived from human adipose tissue. J Bone Miner Res2009; 24(5): 816–825

[80] Vegiopoulos A, Müller-Decker K, Strzoda D, Schmitt I, Chichelnitskiy E, Ostertag A, Berriel Diaz M, Rozman J, Hrabe de Angelis M, Nüsing RM, Meyer CW, Wahli W, Klingenspor M, Herzig S. Cyclooxygenase-2 controls energy homeostasis in mice by de novo recruitment of brown adipocytes. Science2010; 328(5982): 1158–1161

[81] Madsen L, Pedersen LM, Lillefosse HH, Fjaere E, Bronstad I, Hao Q, Petersen RK, Hallenborg P, Ma T, De Matteis R, Araujo P, Mercader J, Bonet ML, Hansen JB, Cannon B, Nedergaard J, Wang J, Cinti S, Voshol P, Døskeland SO, Kristiansen K. UCP1 induction during recruitment of brown adipocytes in white adipose tissue is dependent on cyclooxygenase activity. PLoS ONE2010; 5(6): e11391

[82] Kim JK, Kim HJ, Park SY, Cederberg A, Westergren R, Nilsson D, Higashimori T, Cho YR, Liu ZX, Dong J, Cline GW, Enerback S, Shulman GI. Adipocyte-specific overexpression of FOXC2 prevents diet-induced increases in intramuscular fatty acyl CoA and insulin resistance. Diabetes2005; 54(6): 1657–1663

[83] Xue Y, Cao R, Nilsson D, Chen S, Westergren R, Hedlund EM, Martijn C, Rondahl L, Krauli P, Walum E, Enerbäck S, Cao Y. FOXC2 controls Ang-2 expression and modulates angiogenesis, vascular patterning, remodeling, and functions in adipose tissue. Proc Natl Acad Sci USA2008; 105(29): 10167–10172

[84] Lidell ME, Seifert EL, Westergren R, Heglind M, Gowing A, Sukonina V, Arani Z, Itkonen P, Wallin S, Westberg F, Fernandez-Rodriguez J, Laakso M, Nilsson T, Peng XR, Harper ME, Enerbäck S. The adipocyte-expressed forkhead transcription factor Foxc2 regulates metabolism through altered mitochondrial function. Diabetes2011; 60(2): 427–435

[85] Cederberg A, Grønning LM, Ahrén B, Taskén K, Carlsson P, Enerbäck S. FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. Cell2001; 106(5): 563–573

[86] Dahle MK, Grønning LM, Cederberg A, Blomhoff HK, Miura N, Enerbäck S, Taskén KA, Taskén K. Mechanisms of FOXC2- and FOXD1-mediated regulation of the RI alpha subunit of cAMP-dependent protein kinase include release of transcriptional repression and activation by protein kinase B alpha and cAMP. J Biol Chem2002; 277(25): 22902–22908

[87] Wu J, Cohen P, Spiegelman BM. Adaptive thermogenesis in adipocytes: is beige the new brown? Genes Dev2013; 27(3): 234–250

[88] Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med2013; 19(10): 1252–1263

[89] Pospisilik JA, Schramek D, Schnidar H, Cronin SJ, Nehme NT, Zhang X, Knauf C, Cani PD, Aumayr K, Todoric J, Bayer M, Haschemi A, Puviindran V, Tar K, Orthofer M, Neely GG, Dietzl G, Manoukian A, Funovics M, Prager G, Wagner O, Ferrandon D, Aberger F, Hui CC, Esterbauer H, Penninger JM. Drosophila genome-wide obesity screen reveals hedgehog as a determinant of brown versus white adipose cell fate. Cell2010; 140(1): 148–160

[90] Teperino R, Amann S, Bayer M, McGee SL, Loipetzberger A, Connor T, Jaeger C, Kammerer B, Winter L, Wiche G, Dalgaard K, Selvaraj M, Gaster M, Lee-Young RS, Febbraio MA, Knauf C, Cani PD, Aberger F, Penninger JM, Pospisilik JA, Esterbauer H. Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat. Cell2012; 151(2): 414–426

[91] Kang S, Bajnok L, Longo KA, Petersen RK, Hansen JB, Kristiansen K, MacDougald OA. Effects of Wnt signaling on brown adipocyte differentiation and metabolism mediated by PGC-1alpha. Mol Cell Biol2005; 25(4): 1272–1282

[92] Longo KA, Wright WS, Kang S, Gerin I, Chiang SH, Lucas PC, Opp MR, MacDougald OA. Wnt10b inhibits development of white and brown adipose tissues. J Biol Chem2004; 279(34): 35503–35509

[93] Hondares E, Iglesias R, Giralt A, Gonzalez FJ, Giralt M, Mampel T, Villarroya F. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem2011; 286(15): 12983–12990

[94] Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, Moller DE, Kharitonenkov A. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology2008; 149(12): 6018–6027

[95] Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, Wu J, Kharitonenkov A, Flier JS, Maratos-Flier E, Spiegelman BM. FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes Dev2012; 26(3): 271–281

[96] Chartoumpekis DV, Habeos IG, Ziros PG, Psyrogiannis AI, Kyriazopoulou VE, Papavassiliou AG. Brown adipose tissue responds to cold and adrenergic stimulation by induction of FGF21. Mol Med2011; 17(7–8): 736–740

[97] Tseng YH, Kokkotou E, Schulz TJ, Huang TL, Winnay JN, Taniguchi CM, Tran TT, Suzuki R, Espinoza DO, Yamamoto Y, Ahrens MJ, Dudley AT, Norris AW, Kulkarni RN, Kahn CR. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature2008; 454(7207): 1000–1004

[98] Townsend KL, Suzuki R, Huang TL, Jing E, Schulz TJ, Lee K, Taniguchi CM, Espinoza DO, McDougall LE, Zhang H, He TC, Kokkotou E, Tseng YH. Bone morphogenetic protein 7 (BMP7) reverses obesity and regulates appetite through a central mTOR pathway. FASEB J2012; 26(5): 2187–2196

[99] Whittle AJ, Carobbio S, Martins L, Slawik M, Hondares E, Vázquez MJ, Morgan D, Csikasz RI, Gallego R, Rodriguez-Cuenca S, Dale M, Virtue S, Villarroya F, Cannon B, Rahmouni K, López M, Vidal-Puig A. BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell2012; 149(4): 871–885

[100] Tang QQ, Otto TC, Lane MD. Commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc Natl Acad Sci USA2004; 101(26): 9607–9611

[101] Bowers RR, Kim JW, Otto TC, Lane MD. Stable stem cell commitment to the adipocyte lineage by inhibition of DNA methylation: role of the BMP-4 gene. Proc Natl Acad Sci USA2006; 103(35): 13022–13027

[102] Huang H, Song TJ, Li X, Hu L, He Q, Liu M, Lane MD, Tang QQ. BMP signaling pathway is required for commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc Natl Acad Sci USA2009; 106(31): 12670–12675

[103] Huang HY, Chen SZ, Zhang WT, Wang SS, Liu Y, Li X, Sun X, Li YM, Wen B, Lei QY, Tang QQ. Induction of EMT-like response by BMP4 via up-regulation of lysyl oxidase is required for adipocyte lineage commitment. Stem Cell Res (Amst)2013; 10(3): 278–287

[104] Qian SW, Tang Y, Li X, Liu Y, Zhang YY, Huang HY, Xue RD, Yu HY, Guo L, Gao HD, Liu Y, Sun X, Li YM, Jia WP, Tang QQ. BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis. Proc Natl Acad Sci USA2013; 110(9): E798–E807

[105] Dong M, Yang X, Lim S, Cao Z, Honek J, Lu H, Zhang C, Seki T, Hosaka K, Wahlberg E, Yang J, Zhang L, Länne T, Sun B, Li X, Liu Y, Zhang Y, Cao Y. Cold exposure promotes atherosclerotic plaque growth and instability via UCP1-dependent lipolysis. Cell Metab2013; 18(1): 118–129

[106] van der Lans AA, Hoeks J, Brans B, Vijgen GH, Visser MG, Vosselman MJ, Hansen J, Jörgensen JA, Wu J, Mottaghy FM, Schrauwen P, van Marken Lichtenbelt WD. Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. J Clin Invest2013; 123(8): 3395–3403

[107] Yoneshiro T, Aita S, Matsushita M, Kayahara T, Kameya T, Kawai Y, Iwanaga T, Saito M. Recruited brown adipose tissue as an antiobesity agent in humans. J Clin Invest2013; 123(8): 3404–3408

[108] Dhaka A, Viswanath V, Patapoutian A. Trp ion channels and temperature sensation. Annu Rev Neurosci2006; 29(1): 135–161

[109] Nakamura K. Central circuitries for body temperature regulation and fever. Am J Physiol Regul Integr Comp Physiol2011; 301(5): R1207–R1228

[110] Snitker S, Fujishima Y, Shen H, Ott S, Pi-Sunyer X, Furuhata Y, Sato H, Takahashi M. Effects of novel capsinoid treatment on fatness and energy metabolism in humans: possible pharmacogenetic implications. Am J Clin Nutr2009; 89(1): 45–50

[111] Ludy MJ, Moore GE, Mattes RD. The effects of capsaicin and capsiate on energy balance: critical review and meta-analyses of studies in humans. Chem Senses2012; 37(2): 103–121

[112] Saito M, Yoneshiro T. Capsinoids and related food ingredients activating brown fat thermogenesis and reducing body fat in humans. Curr Opin Lipidol2013; 24(1): 71–77

Acknowledgements

This article based on research that was funded partially by National Basic Research Program of China (Grant No. 2011CB910201; for Q.Q.T.), and National Natural Science Foundation of China (Grant No. 81200621; for S.W.Q).

Shuwen Qian, Haiyan Huang, and Qiqun Tang declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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