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

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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.

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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. Lancet 2014; 384(9945): 766–781

    PubMed  Google Scholar 

  2. Bornfeldt KE, Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab 2011; 14(5): 575–585

    PubMed Central  CAS  PubMed  Google Scholar 

  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. Circulation 2009; 119(3): 480–486

    PubMed  Google Scholar 

  4. Gesta S, Tseng YH, Kahn CR. Developmental origin of fat: tracking obesity to its source. Cell 2007; 131(2): 242–256

    CAS  PubMed  Google Scholar 

  5. Virtanen KA, Nuutila P. Brown adipose tissue in humans. Curr Opin Lipidol 2011; 22(1): 49–54

    CAS  PubMed  Google Scholar 

  6. Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature 2006; 444(7121): 847–853

    PubMed Central  CAS  PubMed  Google Scholar 

  7. Cannon B, Houstek J, Nedergaard J. Brown adipose tissue. More than an effector of thermogenesis? Ann N Y Acad Sci 1998; 856(1 MOLECULAR MEC): 171–187

    CAS  PubMed  Google Scholar 

  8. Villarroya J, Cereijo R, Villarroya F. An endocrine role for brown adipose tissue? Am J Physiol Endocrinol Metab 2013; 305(5): E567–E572

    CAS  PubMed  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  10. Loncar D, Afzelius BA, Cannon B. Epididymal white adipose tissue after cold stress in rats. I. Nonmitochondrial changes. J Ultrastruct Mol Struct Res 1988; 101(2–3): 109–122

    CAS  PubMed  Google Scholar 

  11. Loncar D, Afzelius BA, Cannon B. Epididymal white adipose tissue after cold stress in rats. II. Mitochondrial changes. J Ultrastruct Mol Struct Res 1988; 101(2–3): 199–209

    CAS  PubMed  Google Scholar 

  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 Res 1986; 97(1–3): 119–129

    CAS  PubMed  Google Scholar 

  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 USA 2007; 104(7): 2366–2371

    PubMed Central  CAS  PubMed  Google Scholar 

  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 Res 2007; 48(1): 41–51

    CAS  PubMed  Google Scholar 

  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 Invest 1998; 102(2): 412–420

    PubMed Central  CAS  PubMed  Google Scholar 

  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 Sci 1992; 103(Pt 4): 931–942

    CAS  PubMed  Google Scholar 

  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 Physiol 2000; 279(3): C670–C681

    CAS  PubMed  Google Scholar 

  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 Sci 1998; 54(2): 191–195

    PubMed  Google Scholar 

  19. 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

    CAS  PubMed  Google Scholar 

  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 Med 2009; 360(15): 1509–1517

    PubMed Central  CAS  PubMed  Google Scholar 

  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. Diabetes 2009; 58(7): 1526–1531

    PubMed Central  CAS  PubMed  Google Scholar 

  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 Med 2009; 360(15): 1500–1508

    PubMed  Google Scholar 

  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 Med 2009; 360(15): 1518–1525

    CAS  PubMed  Google Scholar 

  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 J 2009; 23(9): 3113–3120

    CAS  PubMed  Google Scholar 

  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. Nature 2009; 460(7259): 1154–1158

    PubMed Central  CAS  PubMed  Google Scholar 

  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 USA 2007; 104(11): 4401–4406

    PubMed Central  CAS  PubMed  Google Scholar 

  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. Nature 2008; 454(7207): 961–967

    PubMed Central  CAS  PubMed  Google Scholar 

  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. Cell 2012; 150(2): 366–376

    PubMed Central  CAS  PubMed  Google Scholar 

  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 Metab 2012; 302(1): E19–E31

    PubMed  Google Scholar 

  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 ONE 2012; 7(11): e49452

    PubMed Central  CAS  PubMed  Google Scholar 

  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 Med 2013; 19(5): 631–634

    CAS  PubMed  Google Scholar 

  32. Lidell ME, Betz MJ, Enerbäck S. Two types of brown adipose tissue in humans. Adipocyte 2014; 3(1): 63–66

    PubMed Central  PubMed  Google Scholar 

  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 Med 2013; 19(5): 635–639

    PubMed Central  CAS  PubMed  Google Scholar 

  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 Metab 2013; 17(5): 798–805

    CAS  PubMed  Google Scholar 

  35. Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev 2004; 84(1): 277–359

    CAS  PubMed  Google Scholar 

  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 Pharmacol 1979; 57(3): 257–270

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  38. Ghorbani M, Claus TH, Himms-Hagen J. Hypertrophy of brown adipocytes in brown and white adipose tissues and reversal of dietinduced obesity in rats treated with a beta3-adrenoceptor agonist. Biochem Pharmacol 1997; 54(1): 121–131

    CAS  PubMed  Google Scholar 

  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. Nature 1993; 366(6457): 740–742

    CAS  PubMed  Google Scholar 

  40. 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 Commun 1992; 185(3): 1078–1082

    CAS  PubMed  Google Scholar 

  41. 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. Endocrinology 2006; 147(12): 5730–5739

    CAS  PubMed  Google Scholar 

  42. 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 Invest 2013; 123(1): 215–223

    PubMed Central  CAS  PubMed  Google Scholar 

  43. 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 Metab 2011; 96(1): 192–199

    CAS  PubMed  Google Scholar 

  44. Crandall DL, Hausman GJ, Kral JG. A review of the microcirculation of adipose tissue: anatomic, metabolic, and angiogenic perspectives. Microcirculation 1997; 4(2): 211–232

    CAS  PubMed  Google Scholar 

  45. Jansson PA. Endothelial dysfunction in insulin resistance and type 2 diabetes. J Intern Med 2007; 262(2): 173–183

    CAS  PubMed  Google Scholar 

  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. Science 1998; 281(5383): 1683–1686

    CAS  PubMed  Google Scholar 

  47. Cao Y. Angiogenesis modulates adipogenesis and obesity. J Clin Invest 2007; 117(9): 2362–2368

    PubMed Central  CAS  PubMed  Google Scholar 

  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. Endocrinology 2005; 146(10): 4545–4554

    CAS  PubMed  Google Scholar 

  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 Res 2006; 66(23): 11462–11470

    CAS  PubMed  Google Scholar 

  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 USA 2004; 101(8): 2476–2481

    PubMed Central  PubMed  Google Scholar 

  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 USA 2001; 98(11): 6390–6395

    PubMed Central  CAS  PubMed  Google Scholar 

  52. Hausman GJ, Richardson RL. Adipose tissue angiogenesis. J Anim Sci 2004; 82(3): 925–934

    CAS  PubMed  Google Scholar 

  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 omentummediated angiogenesis. J Surg Res 1997; 67(2): 147–154

    CAS  PubMed  Google Scholar 

  54. Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 1999; 13(1): 9–22

    CAS  PubMed  Google Scholar 

  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. Diabetes 2012; 61(7): 1801–1813

    PubMed Central  CAS  PubMed  Google Scholar 

  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 Metab 2013; 17(1): 61–72

    CAS  PubMed  Google Scholar 

  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 USA 2012; 109(15): 5874–5879

    PubMed Central  CAS  PubMed  Google Scholar 

  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 Invest 2014; 124(5): 2099–2112

    PubMed Central  CAS  PubMed  Google Scholar 

  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 Metab 2009; 9(1): 99–109

    CAS  PubMed  Google Scholar 

  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 Invest 2006; 116(12): 3220–3228

    PubMed Central  CAS  PubMed  Google Scholar 

  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 Cell 2008; 3(3): 301–313

    CAS  PubMed  Google Scholar 

  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 Res 2008; 102(1): 77–85

    CAS  PubMed  Google Scholar 

  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 Metab 2012; 15(2): 222–229

    PubMed Central  CAS  PubMed  Google Scholar 

  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. Science 2008; 322(5901): 583–586

    PubMed Central  CAS  PubMed  Google Scholar 

  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

    PubMed  Google Scholar 

  66. 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

    PubMed Central  PubMed  Google Scholar 

  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. Nature 2011; 480(7375): 104–108

    PubMed Central  CAS  PubMed  Google Scholar 

  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. Cell 2014; 157(6): 1292–1308

    CAS  PubMed  Google Scholar 

  69. Nicholls DG. The physiological regulation of uncoupling proteins. Biochim Biophys Acta 2006; 1757(5–6): 459–466

    CAS  PubMed  Google Scholar 

  70. Fedorenko A, Lishko PV, Kirichok Y. Mechanism of fatty-aciddependent UCP1 uncoupling in brown fat mitochondria. Cell 2012; 151(2): 400–413

    PubMed Central  CAS  PubMed  Google Scholar 

  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 Biol 2005; 25(13): 5466–5479

    PubMed Central  CAS  PubMed  Google Scholar 

  72. Bonet ML, Oliver P, Palou A. Pharmacological and nutritional agents promoting browning of white adipose tissue. Biochim Biophys Acta 2013; 1831(5): 969–985

    CAS  PubMed  Google Scholar 

  73. Cao W, Daniel KW, Robidoux J, Puigserver P, Medvedev AV, Bai X, Floering LM, Spiegelman BM, Collins S. p38 mitogenactivated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene. Mol Cell Biol 2004; 24(7): 3057–3067

    PubMed Central  CAS  PubMed  Google Scholar 

  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 Physiol 1982; 242(6): E353–E359

    CAS  PubMed  Google Scholar 

  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 Biol 1986; 64(11): 1125–1134

    CAS  PubMed  Google Scholar 

  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 Anat 2009; 214(1): 171–178

    PubMed Central  CAS  PubMed  Google Scholar 

  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 Biochem 2003; 270(4): 699–705

    CAS  PubMed  Google Scholar 

  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 Biol 2012; 10(4): e1001314

    PubMed Central  CAS  PubMed  Google Scholar 

  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 Res 2009; 24(5): 816–825

    CAS  PubMed  Google Scholar 

  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. Science 2010; 328(5982): 1158–1161

    CAS  PubMed  Google Scholar 

  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 ONE 2010; 5(6): e11391

    PubMed Central  PubMed  Google Scholar 

  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. Diabetes 2005; 54(6): 1657–1663

    CAS  PubMed  Google Scholar 

  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 USA 2008; 105(29): 10167–10172

    PubMed Central  CAS  PubMed  Google Scholar 

  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. Diabetes 2011; 60(2): 427–435

    PubMed Central  CAS  PubMed  Google Scholar 

  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. Cell 2001; 106(5): 563–573

    CAS  PubMed  Google Scholar 

  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 Chem 2002; 277(25): 22902–22908

    CAS  PubMed  Google Scholar 

  87. Wu J, Cohen P, Spiegelman BM. Adaptive thermogenesis in adipocytes: is beige the new brown? Genes Dev 2013; 27(3): 234–250

    PubMed Central  CAS  PubMed  Google Scholar 

  88. Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med 2013; 19(10): 1252–1263

    CAS  PubMed  Google Scholar 

  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. Cell 2010; 140(1): 148–160

    CAS  PubMed  Google Scholar 

  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. Cell 2012; 151(2): 414–426

    CAS  PubMed  Google Scholar 

  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 Biol 2005; 25(4): 1272–1282

    PubMed Central  CAS  PubMed  Google Scholar 

  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 Chem 2004; 279(34): 35503–35509

    CAS  PubMed  Google Scholar 

  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 Chem 2011; 286(15): 12983–12990

    PubMed Central  CAS  PubMed  Google Scholar 

  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. Endocrinology 2008; 149(12): 6018–6027

    CAS  PubMed  Google Scholar 

  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 Dev 2012; 26(3): 271–281

    PubMed Central  CAS  PubMed  Google Scholar 

  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 Med 2011; 17(7–8): 736–740

    PubMed Central  CAS  PubMed  Google Scholar 

  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. Nature 2008; 454(7207): 1000–1004

    PubMed Central  CAS  PubMed  Google Scholar 

  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 J 2012; 26(5): 2187–2196

    PubMed Central  CAS  PubMed  Google Scholar 

  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. Cell 2012; 149(4): 871–885

    PubMed Central  CAS  PubMed  Google Scholar 

  100. Tang QQ, Otto TC, Lane MD. Commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc Natl Acad Sci USA 2004; 101(26): 9607–9611

    PubMed Central  CAS  PubMed  Google Scholar 

  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 USA 2006; 103(35): 13022–13027

    PubMed Central  CAS  PubMed  Google Scholar 

  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 C 3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc Natl Acad Sci USA 2009; 106(31): 12670–12675

    PubMed Central  CAS  PubMed  Google Scholar 

  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

    CAS  Google Scholar 

  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 USA 2013; 110(9): E798–E807

    PubMed Central  CAS  PubMed  Google Scholar 

  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 Metab 2013; 18(1): 118–129

    PubMed Central  CAS  PubMed  Google Scholar 

  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 Invest 2013; 123(8): 3395–3403

    PubMed Central  PubMed  Google Scholar 

  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 Invest 2013; 123(8): 3404–3408

    PubMed Central  CAS  PubMed  Google Scholar 

  108. Dhaka A, Viswanath V, Patapoutian A. Trp ion channels and temperature sensation. Annu Rev Neurosci 2006; 29(1): 135–161

    CAS  PubMed  Google Scholar 

  109. Nakamura K. Central circuitries for body temperature regulation and fever. Am J Physiol Regul Integr Comp Physiol 2011; 301(5): R1207–R1228

    CAS  PubMed  Google Scholar 

  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 Nutr 2009; 89(1): 45–50

    PubMed Central  CAS  PubMed  Google Scholar 

  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 Senses 2012; 37(2): 103–121

    PubMed Central  CAS  PubMed  Google Scholar 

  112. Saito M, Yoneshiro T. Capsinoids and related food ingredients activating brown fat thermogenesis and reducing body fat in humans. Curr Opin Lipidol 2013; 24(1): 71–77

    CAS  PubMed  Google Scholar 

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  1. Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education; Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, 200032, China

    Shuwen Qian, Haiyan Huang & Qiqun Tang

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  1. Shuwen Qian
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Qian, S., Huang, H. & Tang, Q. Brown and beige fat: the metabolic function, induction, and therapeutic potential. Front. Med. 9, 162–172 (2015). https://doi.org/10.1007/s11684-015-0382-2

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