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Frontiers of Medicine

, Volume 12, Issue 2, pp 130–138 | Cite as

Role of brown adipose tissue in metabolic syndrome, aging, and cancer cachexia

  • Meng Dong
  • Jun Lin
  • Wonchung Lim
  • Wanzhu Jin
  • Hyuek Jong Lee
Review

Abstract

Brown adipose tissue (BAT) plays a fundamental role in maintaining body temperature by producing heat. BAT that had been know to exist only in mammals and the human neonate has received great attention for the treatment of obesity and diabetes due to its important function in energy metabolism, ever since it is recently reported that human adults have functional BAT. In addition, beige adipocytes, brown adipocytes in white adipose tissue (WAT), have also been shown to take part in whole body metabolism. Multiple lines of evidence demonstrated that transplantation or activation of BAT or/and beige adipocytes reversed obesity and improved insulin sensitivity. Furthermore, many genes involved in BATactivation and/or the recruitment of beige cells have been found, thereby providing new promising strategies for future clinical application of BAT activation to treat obesity and metabolic diseases. This review focuses on recent advances of BAT function in the metabolic aspect and the relationship between BAT and cancer cachexia, a pathological process accompanied with decreased body weight and increased energy expenditure in cancer patients. The underlying possible mechanisms to reduce BAT mass and its activity in the elderly are also discussed.

Keywords

brown adipose tissue beige adipocyte anti-obesity anti-diabetes cancer cachexia aging 

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Notes

Acknowledgements

This work was supported by the Strategic Priority Research Program (No. XDB13030000), the Ministry of Science and Technology of China (Nos. 2015CB943102, 2012CBA01301, and 2012CB944701), and the National Natural Science Foundation of China (No. 81370951).

References

  1. 1.
    Schulz TJ, Tseng YH. Emerging role of bone morphogenetic proteins in adipogenesis and energy metabolism. Cytokine Growth Factor Rev 2009; 20(5-6): 523–531PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Townsend KL, Tseng YH. Brown fat fuel utilization and thermogenesis. Trends Endocrinol Metab 2014; 25(4): 168–177PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Shen YY, Liu XM, Dong M, Lin J, Zhao QW, Lee H, Jin WZ. Recent advances in brown adipose tissue biology. Chin Sci Bull 2014; 59(31): 4030–4040CrossRefGoogle Scholar
  4. 4.
    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): 1509–1517PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    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): 1500–1508PubMedCrossRefGoogle Scholar
  6. 6.
    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): 1518–1525PubMedCrossRefGoogle Scholar
  7. 7.
    Oelkrug R, Polymeropoulos ET, Jastroch M. Brown adipose tissue: physiological function and evolutionary significance. J Comp Physiol B 2015; 185(6): 587–606PubMedCrossRefGoogle Scholar
  8. 8.
    Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev 2004; 84(1): 277–359PubMedCrossRefGoogle Scholar
  9. 9.
    Astrup A. Thermogenesis in human brown adipose tissue and skeletal muscle induced by sympathomimetic stimulation. Acta Endocrinol Suppl (Copenh) 1986; 278: 1–32Google Scholar
  10. 10.
    Adamson SK Jr, Towell ME. Thermal homeostasis in the fetus and newborn. Anesthesiology 1965; 26(4): 531–548PubMedCrossRefGoogle Scholar
  11. 11.
    Asakura H. Fetal and neonatal thermoregulation. J Nippon Med Sch 2004; 71(6): 360–370PubMedCrossRefGoogle Scholar
  12. 12.
    Symonds ME. Pregnancy, parturition and neonatal development: interactions between nutrition and thyroid hormones. Proc Nutr Soc 1995; 54(2): 329–343PubMedCrossRefGoogle Scholar
  13. 13.
    Aherne W, Hull D. Brown adipose tissue and heat production in the newborn infant. J Pathol Bacteriol 1966; 91(1): 223–234PubMedCrossRefGoogle Scholar
  14. 14.
    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): 4401–4406PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    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): 961–967PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Lepper C, Fan CM. Inducible lineage tracing of Pax7-descendant cells reveals embryonic origin of adult satellite cells. Genesis 2010; 48(7): 424–436PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    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-ß transcriptional complex. Nature 2009; 460(7259): 1154–1158PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    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): 395–404PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    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): 366–376PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Lee YH, Petkova AP, Mottillo EP, Granneman JG. In vivo identification of bipotential adipocyte progenitors recruited by ß3-adrenoceptor activation and high-fat feeding. Cell Metab 2012; 15(4): 480–491PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    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): 798–805PubMedCrossRefGoogle Scholar
  22. 22.
    Seale P, Kajimura S, Yang W, Chin S, Rohas LM, Uldry M, Tavernier G, Langin D, Spiegelman BM. Transcriptional control of brown fat determination by PRDM16. Cell Metab 2007; 6(1): 38–54PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Dalgaard LT, Pedersen O. Uncoupling proteins: functional characteristics and role in the pathogenesis of obesity and Type II diabetes. Diabetologia 2001; 44(8): 946–965PubMedCrossRefGoogle Scholar
  24. 24.
    Ricquier D. Respiration uncoupling and metabolism in the control of energy expenditure. Proc Nutr Soc 2005; 64(1): 47–52PubMedCrossRefGoogle Scholar
  25. 25.
    Enerbäck S, Jacobsson A, Simpson EM, Guerra C, Yamashita H, Harper ME, Kozak LP. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 1997; 387(6628): 90–94PubMedCrossRefGoogle Scholar
  26. 26.
    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): 203–209PubMedCrossRefGoogle Scholar
  27. 27.
    Orava J, Nuutila P, Noponen T, Parkkola R, Viljanen T, Enerbäck S, Rissanen A, Pietiläinen KH, Virtanen KA. Blunted metabolic responses to cold and insulin stimulation in brown adipose tissue of obese humans. Obesity (Silver Spring) 2013; 21(11): 2279–2287CrossRefGoogle Scholar
  28. 28.
    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): 1278–1283PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    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–E606PubMedCrossRefGoogle Scholar
  30. 30.
    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): 215–223PubMedCrossRefGoogle Scholar
  31. 31.
    Liu X, Zheng Z, Zhu X, Meng M, Li L, Shen Y, Chi Q, Wang D, Zhang Z, Li C, Li Y, Xue Y, Speakman JR, Jin W. Brown adipose tissue transplantation improves whole-body energy metabolism. Cell Res 2013; 23(6): 851–854PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Zhu Z, Spicer EG, Gavini CK, Goudjo-Ako AJ, Novak CM, Shi H. Enhanced sympathetic activity in mice with brown adipose tissue transplantation (transBATation). Physiol Behav 2014; 125: 21–29PubMedCrossRefGoogle Scholar
  33. 33.
    Liu X, Wang S, You Y, Meng M, Zheng Z, Dong M, Lin J, Zhao Q, Zhang C, Yuan X, Hu T, Liu L, Huang Y, Zhang L, Wang D, Zhan J, Jong Lee H, Speakman JR, Jin W. Brown adipose tissue transplantation reverses obesity in Ob/Ob mice. Endocrinology 2015; 156(7): 2461–2469PubMedCrossRefGoogle Scholar
  34. 34.
    Kim EH, Heo CY. Current applications of adipose-derived stem cells and their future perspectives. World J Stem Cells 2014; 6(1): 65–68PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med 2013; 19(10): 1252–1263PubMedCrossRefGoogle Scholar
  36. 36.
    Vallerand AL, Lupien J, Bukowiecki LJ. Cold exposure reverses the diabetogenic effects of high-fat feeding. Diabetes 1986; 35(3): 329–334PubMedCrossRefGoogle Scholar
  37. 37.
    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): 3404–3408PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    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): 171–178PubMedCrossRefGoogle Scholar
  39. 39.
    Collins S. b-Adrenoceptor signaling networks in adipocytes for recruiting stored fat and energy expenditure. Front Endocrinol (Lausanne) 2012; 2: 102Google Scholar
  40. 40.
    Giordano A, Frontini A, Murano I, Tonello C, Marino MA, Carruba MO, Nisoli E, Cinti S. Regional-dependent increase of sympathetic innervation in rat white adipose tissue during prolonged fasting. J Histochem Cytochem 2005; 53(6): 679–687PubMedCrossRefGoogle Scholar
  41. 41.
    Barbatelli G, Murano I, Madsen L, Hao Q, Jimenez M, Kristiansen K, Giacobino JP, De Matteis R, Cinti S. The emergence of coldinduced 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–E1253PubMedCrossRefGoogle Scholar
  42. 42.
    Liu X, Pérußse F, Bukowiecki LJ. Mechanisms of the antidiabetic effects of the ß 3-adrenergic agonist CL-316243 in obese Zucker-ZDF rats. Am J Physiol 1998; 274(5 Pt 2): R1212–R1219PubMedCrossRefGoogle Scholar
  43. 43.
    de Souza CJ, Hirshman MF, Horton ES. CL-316,243, a ß3-specific adrenoceptor agonist, enhances insulin-stimulated glucose disposal in nonobese rats. Diabetes 1997; 46(8): 1257–1263PubMedCrossRefGoogle Scholar
  44. 44.
    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): 1292–1308PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Lee SD, Tontonoz P. Eosinophils in fat: pink is the new brown. Cell 2014; 157(6): 1249–1250PubMedCrossRefGoogle Scholar
  46. 46.
    Brestoff JR, Kim BS, Saenz SA, Stine RR, Monticelli LA, Sonnenberg GF, Thome JJ, Farber DL, Lutfy K, Seale P, Artis D. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 2015; 519(7542): 242–246PubMedCrossRefGoogle Scholar
  47. 47.
    Xu J, Lloyd DJ, Hale C, Stanislaus S, Chen M, Sivits G, Vonderfecht S, Hecht R, Li YS, Lindberg RA, Chen JL, Jung DY, Zhang Z, Ko HJ, Kim JK, Véniant MM. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 2009; 58(1): 250–259PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    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): 6018–6027PubMedCrossRefGoogle Scholar
  49. 49.
    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–E807PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    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): 1000–1004PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    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): 871–885PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Bordicchia M, Liu D, Amri EZ, Ailhaud G, Dessì-Fulgheri P, Zhang C, Takahashi N, Sarzani R, Collins S. 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): 1022–1036PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Gaich G, Chien JY, Fu H, Glass LC, Deeg MA, Holland WL, Kharitonenkov A, Bumol T, Schilske HK, Moller DE. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab 2013; 18(3): 333–340PubMedCrossRefGoogle Scholar
  54. 54.
    Kawabata F, Inoue N, Yazawa S, Kawada T, Inoue K, Fushiki T. Effects of CH-19 sweet, a non-pungent cultivar of red pepper, in decreasing the body weight and suppressing body fat accumulation by sympathetic nerve activation in humans. Biosci Biotechnol Biochem 2006; 70(12): 2824–2835PubMedCrossRefGoogle Scholar
  55. 55.
    Kawada T, Watanabe T, Takaishi T, Tanaka T, Iwai K. Capsaicininduced beta-adrenergic action on energy metabolism in rats: influence of capsaicin on oxygen consumption, the respiratory quotient, and substrate utilization. Proc Soc Exp Biol Med 1986; 183(2): 250–256PubMedCrossRefGoogle Scholar
  56. 56.
    Kawada T, Hagihara K, Iwai K. Effects of capsaicin on lipid metabolism in rats fed a high fat diet. J Nutr 1986; 116(7): 1272–1278PubMedCrossRefGoogle Scholar
  57. 57.
    Ohnuki K, Haramizu S, Oki K, Watanabe T, Yazawa S, Fushiki T. Administration of capsiate, a non-pungent capsaicin analog, promotes energy metabolism and suppresses body fat accumulation in mice. Biosci Biotechnol Biochem 2001; 65(12): 2735–2740PubMedCrossRefGoogle Scholar
  58. 58.
    Masuda Y, Haramizu S, Oki K, Ohnuki K, Watanabe T, Yazawa S, Kawada T, Hashizume S, Fushiki T. Upregulation of uncoupling proteins by oral administration of capsiate, a nonpungent capsaicin analog. J Appl Physiol (1985) 2003;95(6): 2408–2415CrossRefGoogle Scholar
  59. 59.
    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): 118–129PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Berbée JF, Boon MR, Khedoe PP, Bartelt A, Schlein C, Worthmann A, Kooijman S, Hoeke G, Mol IM, John C, Jung C, Vazirpanah N, Brouwers LP, Gordts PL, Esko JD, Hiemstra PS, Havekes LM, Scheja L, Heeren J, Rensen PC. Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development. Nat Commun 2015; 6: 6356PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, Kaul MG, Tromsdorf UI, Weller H, Waurisch C, Eychmüller A, Gordts PL, Rinninger F, Bruegelmann K, Freund B, Nielsen P, Merkel M, Heeren J. Brown adipose tissue activity controls triglyceride clearance. Nat Med 2011; 17(2): 200–205PubMedCrossRefGoogle Scholar
  62. 62.
    Carey AL, Kingwell BA. Brown adipose tissue in humans: therapeutic potential to combat obesity. Pharmacol Ther 2013; 140(1): 26–33PubMedCrossRefGoogle Scholar
  63. 63.
    Gunawardana SC, Piston DW. Reversal of type 1 diabetes in mice by brown adipose tissue transplant. Diabetes 2012; 61(3): 674–682PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Gunawardana SC, Piston DW. Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown adipose tissue transplant. Am J Physiol Endocrinol Metab 2015; 308(12): E1043–E1055PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Min SY, Kady J, Nam M, Rojas-Rodriguez R, Berkenwald A, Kim JH, Noh HL, Kim JK, Cooper MP, Fitzgibbons T, Brehm MA, Corvera S. Human ‘brite/beige’ adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice. Nat Med 2016; 22(3): 312–318PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Nishio M, Yoneshiro T, Nakahara M, Suzuki S, Saeki K, Hasegawa M, Kawai Y, Akutsu H, Umezawa A, Yasuda K, Tobe K, Yuo A, Kubota K, Saito M, Saeki K. Production of functional classical brown adipocytes from human pluripotent stem cells using specific hemopoietin cocktail without gene transfer. Cell Metab 2012; 16(3): 394–406PubMedCrossRefGoogle Scholar
  67. 67.
    Nishio M, Saeki K. Differentiation of human pluripotent stem cells into highly functional classical brown adipocytes. Methods Enzymol 2014; 537: 177–197PubMedCrossRefGoogle Scholar
  68. 68.
    Orava J, Nuutila P, Lidell ME, Oikonen V, Noponen T, Viljanen T, Scheinin M, Taittonen M, Niemi T, Enerbäck S, Virtanen KA. Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metab 2011; 14(2): 272–279PubMedCrossRefGoogle Scholar
  69. 69.
    Chondronikola M, Volpi E, Børsheim E, Porter C, Annamalai P, Enerbäck S, Lidell ME, Saraf MK, Labbe SM, Hurren NM, Yfanti C, Chao T, Andersen CR, Cesani F, Hawkins H, Sidossis LS. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes 2014; 63(12): 4089–4099PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Peirce V, Vidal-Puig A. Regulation of glucose homoeostasis by brown adipose tissue. Lancet Diabetes Endocrinol 2013; 1(4): 353–360PubMedCrossRefGoogle Scholar
  71. 71.
    Villarroya J, Cereijo R, Villarroya F. An endocrine role for brown adipose tissue? Am J Physiol Endocrinol Metab 2013; 305(5): E567–E572PubMedCrossRefGoogle Scholar
  72. 72.
    Wang GX, Zhao XY, Lin JD. The brown fat secretome: metabolic functions beyond thermogenesis. Trends Endocrinol Metab 2015; 26(5): 231–237PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    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): 12983–12990PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, Sandusky GE, Hammond LJ, Moyers JS, Owens RA, Gromada J, Brozinick JT, Hawkins ED, Wroblewski VJ, Li DS, Mehrbod F, Jaskunas SR, Shanafelt AB. FGF-21 as a novel metabolic regulator. J Clin Invest 2005; 115(6): 1627–1635PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, Li Y, Goetz R, Mohammadi M, Esser V, Elmquist JK, Gerard RD, Burgess SC, Hammer RE, Mangelsdorf DJ, Kliewer SA. Endocrine regulation of the fasting response by PPARa-mediated induction of fibroblast growth factor 21. Cell Metab 2007; 5(6): 415–425PubMedCrossRefGoogle Scholar
  76. 76.
    Li G, Klein RL, Matheny M, King MA, Meyer EM, Scarpace PJ. Induction of uncoupling protein 1 by central interleukin-6 gene delivery is dependent on sympathetic innervation of brown adipose tissue and underlies one mechanism of body weight reduction in rats. Neuroscience 2002; 115(3): 879–889PubMedCrossRefGoogle Scholar
  77. 77.
    Wallenius V, Wallenius K, Ahrén B, Rudling M, Carlsten H, Dickson SL, Ohlsson C, Jansson JO. Interleukin-6-deficient mice develop mature-onset obesity. Nat Med 2002; 8(1): 75–79PubMedCrossRefGoogle Scholar
  78. 78.
    Virtue S, Feldmann H, Christian M, Tan CY, Masoodi M, Dale M, Lelliott C, Burling K, Campbell M, Eguchi N, Voshol P, Sethi JK, Parker M, Urade Y, Griffin JL, Cannon B, Vidal-Puig A. A new role for lipocalin prostaglandin d synthase in the regulation of brown adipose tissue substrate utilization. Diabetes 2012; 61(12): 3139–3147PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Wang GX, Zhao XY, Meng ZX, Kern M, Dietrich A, Chen Z, Cozacov Z, Zhou D, Okunade AL, Su X, Li S, Blüher M, Lin JD. The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis. Nat Med 2014; 20(12): 1436–1443PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    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): 1801–1813PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Sun K, Kusminski CM, Luby-Phelps K, Spurgin SB, An YA, Wang QA, Holland WL, Scherer PE. Brown adipose tissue derived VEGF-A modulates cold tolerance and energy expenditure. Mol Metab 2014; 3(4): 474–483PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Hagberg CE, Falkevall A, Wang X, Larsson E, Huusko J, Nilsson I, van Meeteren LA, Samen E, Lu L, Vanwildemeersch M, Klar J, Genove G, Pietras K, Stone-Elander S, Claesson-Welsh L, Ylä- Herttuala S, Lindahl P, Eriksson U. Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature 2010; 464(7290): 917–921PubMedCrossRefGoogle Scholar
  83. 83.
    Robciuc MR, Kivelä R, Williams IM, de Boer JF, van Dijk TH, Elamaa H, Tigistu-Sahle F, Molotkov D, Leppänen VM, Käkelä R, Eklund L, Wasserman DH, Groen AK, Alitalo K. VEGFB/VEGFR1-induced expansion of adipose vasculature counteracts obesity and related metabolic complications. Cell Metab 2016; 23(4): 712–724PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    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): e49452PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Rogers NH. Brown adipose tissue during puberty and with aging. Ann Med 2015; 47(2): 142–149PubMedCrossRefGoogle Scholar
  86. 86.
    Heaton JM. The distribution of brown adipose tissue in the human. J Anat 1972; 112(Pt 1): 35–39PubMedPubMedCentralGoogle Scholar
  87. 87.
    Brooke OG, Harris M, Salvosa CB. The response of malnourished babies to cold. J Physiol 1973; 233(1): 75–91PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Graja A, Schulz TJ. Mechanisms of aging-related impairment of brown adipocyte development and function. Gerontology 2015; 61(3): 211–217PubMedCrossRefGoogle Scholar
  89. 89.
    Wallace DC, Fan W, Procaccio V. Mitochondrial energetics and therapeutics. Annu Rev Pathol 2010; 5(1): 297–348PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Kindred JH, Tuulari JJ, Simon S, Luckasen GJ, Bell C, Rudroff T. Brown adipose and central nervous system glucose uptake is lower during cold exposure in older compared to young men: a preliminary PET study. Aging Clin Exp Res 2016; 28(3): 557–560PubMedCrossRefGoogle Scholar
  91. 91.
    Zhang Y, Xie Y, Berglund ED, Coate KC, He TT, Katafuchi T, Xiao G, Potthoff MJ, Wei W, Wan Y, Yu RT, Evans RM, Kliewer SA, Mangelsdorf DJ. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. eLife 2012; 1: e00065PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Chau MD, Gao J, Yang Q, Wu Z, Gromada J. Fibroblast growth factor 21 regulates energy metabolism by activating the AMPKSIRT1-PGC-1a pathway. Proc Natl Acad Sci USA 2010; 107(28): 12553–12558PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Solon-Biet SM, Mitchell SJ, de Cabo R, Raubenheimer D, Le Couteur DG, Simpson SJ. Macronutrients and caloric intake in health and longevity. J Endocrinol 2015; 226(1): R17–R28PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Lee P, Linderman JD, Smith S, Brychta RJ, Wang J, Idelson C, Perron RM, Werner CD, Phan GQ, Kammula US, Kebebew E, Pacak K, Chen KY, Celi FS. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab 2014; 19(2): 302–309PubMedCrossRefGoogle Scholar
  95. 95.
    Youm YH, Horvath TL, Mangelsdorf DJ, Kliewer SA, Dixit VD. Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution. Proc Natl Acad Sci USA 2016; 113(4): 1026–1031PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, Jatoi A, Loprinzi C, Mac Donald N, Mantovani G, Davis M, Muscaritoli M, Ottery F, Radbruch L, Ravasco P, Walsh D, Wilcock A, Kaasa S, Baracos VE. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 2011; 12(5): 489–495PubMedCrossRefGoogle Scholar
  97. 97.
    Cao DX, Wu GH, Zhang B, Quan YJ, Wei J, Jin H, Jiang Y, Yang ZA. Resting energy expenditure and body composition in patients with newly detected cancer. Clin Nutr 2010; 29(1): 72–77PubMedCrossRefGoogle Scholar
  98. 98.
    Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev 2009; 89(2): 381–410PubMedCrossRefGoogle Scholar
  99. 99.
    Brooks SL, Neville AM, Rothwell NJ, Stock MJ, Wilson S. Sympathetic activation of brown-adipose-tissue thermogenesis in cachexia. Biosci Rep 1981; 1(6): 509–517PubMedCrossRefGoogle Scholar
  100. 100.
    Tsoli M, Moore M, Burg D, Painter A, Taylor R, Lockie SH, Turner N, Warren A, Cooney G, Oldfield B, Clarke S, Robertson G. Activation of thermogenesis in brown adipose tissue and dysregulated lipid metabolism associated with cancer cachexia in mice. Cancer Res 2012; 72(17): 4372–4382PubMedCrossRefGoogle Scholar
  101. 101.
    Fueger BJ, Czernin J, Hildebrandt I, Tran C, Halpern BS, Stout D, Phelps ME, Weber WA. Impact of animal handling on the results of 18F-FDG PET studies in mice. J Nucl Med 2006; 47(6): 999–1006PubMedGoogle Scholar
  102. 102.
    Kir S, White JP, Kleiner S, Kazak L, Cohen P, Baracos VE, Spiegelman BM. Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature 2014; 513(7516): 100–104PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Petruzzelli M, Schweiger M, Schreiber R, Campos-Olivas R, Tsoli M, Allen J, Swarbrick M, Rose-John S, Rincon M, Robertson G, Zechner R, Wagner EF. A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metab 2014; 20(3): 433–447PubMedCrossRefGoogle Scholar
  104. 104.
    Knudsen JG, Murholm M, Carey AL, Biensø RS, Basse AL, Allen TL, Hidalgo J, Kingwell BA, Febbraio MA, Hansen JB, Pilegaard H. Role of IL-6 in exercise training-and cold-induced UCP1 expression in subcutaneous white adipose tissue. PLoS One 2014; 9(1): e84910PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Shellock FG, Riedinger MS, Fishbein MC. Brown adipose tissue in cancer patients: possible cause of cancer-induced cachexia. J Cancer Res Clin Oncol 1986; 111(1): 82–85PubMedCrossRefGoogle Scholar
  106. 106.
    Vosselman MJ, Hoeks J, Brans B, Pallubinsky H, Nascimento EB, van der Lans AA, Broeders EP, Mottaghy FM, Schrauwen P, van Marken Lichtenbelt WD. Low brown adipose tissue activity in endurance-trained compared with lean sedentary men. Int J Obes 2015; 39(12): 1696–1702CrossRefGoogle Scholar
  107. 107.
    Hondares E, Rosell M, Gonzalez FJ, Giralt M, Iglesias R, Villarroya F. Hepatic FGF21 expression is induced at birth via PPARa in response to milk intake and contributes to thermogenic activation of neonatal brown fat. Cell Metab 2010; 11(3): 206–212PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Douris N, Stevanovic DM, Fisher FM, Cisu TI, Chee MJ, Nguyen NL, Zarebidaki E, Adams AC, Kharitonenkov A, Flier JS, Bartness TJ, Maratos-Flier E. Central fibroblast growth factor 21 browns white fat via sympathetic action in male mice. Endocrinology 2015; 156(7): 2470–2481PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    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-1a and browning of white adipose tissues in adaptive thermogenesis. Genes Dev 2012; 26(3): 271–281PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Rao RR, Long JZ, White JP, Svensson KJ, Lou J, Lokurkar I, Jedrychowski MP, Ruas JL, Wrann CD, Lo JC, Camera DM, Lachey J, Gygi S, Seehra J, Hawley JA, Spiegelman BM. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 2014; 157(6): 1279–1291PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Lee MW, Odegaard JI, Mukundan L, Qiu Y, Molofsky AB, Nussbaum JC, Yun K, Locksley RM, Chawla A. Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell 2015; 160 (1-2): 74–87PubMedCrossRefGoogle Scholar
  112. 112.
    Hui X, Gu P, Zhang J, Nie T, Pan Y, Wu D, Feng T, Zhong C, Wang Y, Lam KS, Xu A. Adiponectin enhances cold-induced browning of subcutaneous adipose tissue via promoting M2 macrophage proliferation. Cell Metab 2015; 22(2): 279–290PubMedCrossRefGoogle Scholar
  113. 113.
    Schulz TJ, Huang P, Huang TL, Xue R, McDougall LE, Townsend KL, Cypess AM, Mishina Y, Gussoni E, Tseng YH. Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat. Nature 2013; 495(7441): 379–383PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Elsen M, Raschke S, Tennagels N, Schwahn U, Jelenik T, Roden M, Romacho T, Eckel J. BMP4 and BMP7 induce the white-tobrown transition of primary human adipose stem cells. Am J Physiol Cell Physiol 2014; 306(5): C431–C440PubMedCrossRefGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag GmbH Germany 2018

Authors and Affiliations

  • Meng Dong
    • 1
    • 2
  • Jun Lin
    • 1
    • 2
  • Wonchung Lim
    • 3
  • Wanzhu Jin
    • 1
  • Hyuek Jong Lee
    • 1
    • 4
  1. 1.Key Laboratory of Animal Ecology and Conservation Biology, Institute of ZoologyChinese Academy of SciencesBeijingChina
  2. 2.The University of the Chinese Academy of SciencesBeijingChina
  3. 3.Department of Sports Medicine, College of Health ScienceCheongju UniversityCheongjuRepublic of Korea
  4. 4.Center for Vascular ResearchInstitute for Basic Science (IBS)DaejeonRepublic of Korea

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