Advertisement

Brown Adipose Tissue

  • Martin KlingensporEmail author
  • Tobias Fromme

Abstract

A constant body temperature can only be maintained when the rate of heat dissipation equals the rate of heat loss. Thermoregulatory heat production mechanisms compensating heat loss are classically categorized as shivering and non-shivering thermogenesis. Non-shivering thermogenesis occurs in brown adipose tissue, a unique heater organ only found in mammals. In brown adipose tissue mitochondria, the proton motive force across the inner membrane is dissipated as heat rather than converted to ATP. This tightly regulated process is catalyzed by the uncoupling protein 1. Non-shivering thermogenesis is elicited by the sympathetic innervation from hypothalamic and brain stem control regions which are activated by cold sensation. In a cold environment, up to half of the metabolic rate of rodents can be attributed to non-shivering thermogenesis in brown adipose tissue. The high thermogenic capacity of brown adipose tissue recruited in the defense of normothermia may also play a role in the regulation of energy balance in the face of hypercaloric nutrition. In this light, the recent discovery of significant amounts of metabolically active brown adipose tissue in healthy adult humans reintroduces an old player in human energy balance research and may enable new strategies to prevent excess body fat accumulation in man.

Keywords

Uncoupling protein 1 Brown adipose tissue White adipose tissue Adipocyte Progenitor Mitochondria ATP synthesis Non-shivering thermogenesis Progenitor Proliferation Differentiation 

Notes

Acknowledgements

The authors receive financial support from the Else Kröner-Fresenius Stiftung, the German Research Community (Deutsche Forschungsgemeinschaft) and the Federal Ministry for Education and Research (Bundesministerium für Bildung und Forschung).

References

  1. Aquila H, Link TA, Klingenberg M (1985) The uncoupling protein from brown fat mitochondria is related to the mitochondrial ADP/ATP carrier. Analysis of sequence homologies and of folding of the protein in the membrane. EMBO J 4(9):2369–2376PubMedGoogle Scholar
  2. Asano A, Morimatsu M, Nikami H, Yoshida T, Saito M (1997) Adrenergic activation of vascular endothelial growth factor mRNA expression in rat brown adipose tissue: implication in cold-induced angiogenesis. Biochem J 328(Pt 1):179–183PubMedGoogle Scholar
  3. Astrup A, Bulow J, Christensen NJ, Madsen J (1984) Ephedrine-induced thermogenesis in man: no role for interscapular brown adipose tissue. Clin Sci (Lond) 66(2):179–186Google Scholar
  4. Au-Yong IT, Thorn N, Ganatra R, Perkins AC, Symonds ME (2009) Brown adipose tissue and seasonal variation in humans. Diabetes 58(11):2583–2587PubMedCrossRefGoogle Scholar
  5. Bamshad M, Song CK, Bartness TJ (1999) CNS origins of the sympathetic nervous system outflow to brown adipose tissue. Am J Physiol 276(6 Pt 2):R1569–R1578PubMedGoogle Scholar
  6. Barbatelli G, Murano I, Madsen L, Hao Q, Jimenez M, Kristiansen K, Giacobino JP, De MR, Cinti S (2010) The emergence of cold-induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation. Am J Physiol Endocrinol Metab 298(6):E1244–E1253PubMedCrossRefGoogle Scholar
  7. Bargmann W, Vonhehn G, Lindner E (1968) Cells of brown adipose tissue and its innervation. Z Zellforsch Mikrosk Anat 85(4):601PubMedCrossRefGoogle Scholar
  8. Bartness TJ, Vaughan CH, Song CK (2010) Sympathetic and sensory innervation of brown adipose tissue. Int J Obes (Lond) 34(Suppl 1):S36–S42CrossRefGoogle Scholar
  9. Berg F, Gustafson U, Andersson L (2006) The uncoupling protein 1 gene (UCP1) is disrupted in the pig lineage: a genetic explanation for poor thermoregulation in piglets. PLoS Genet 2(8):e129PubMedCrossRefGoogle Scholar
  10. Bouillaud F, Weissenbach J, Ricquier D (1986) Complete cDNA-derived amino acid sequence of rat brown fat uncoupling protein. J Biol Chem 261(4):1487–1490PubMedGoogle Scholar
  11. Bukowiecki L, Collet AJ, Follea N, Guay G, Jahjah L (1982) Brown adipose tissue hyperplasia: a fundamental mechanism of adaptation to cold and hyperphagia. Am J Physiol 242(6):E353–E359PubMedGoogle Scholar
  12. Canettieri G, Celi FS, Baccheschi G, Salvatori L, Andreoli M, Centanni M (2000) Isolation of human type 2 deiodinase gene promoter and characterization of a functional cyclic adenosine monophosphate response element. Endocrinology 141(5):1804–1813PubMedCrossRefGoogle Scholar
  13. Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84(1):277–359PubMedCrossRefGoogle Scholar
  14. Cao W, Daniel KW, Robidoux J, Puigserver P, Medvedev AV, Bai X, Floering LM, Spiegelman BM, Collins S (2004) p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene. Mol Cell Biol 24(7):3057–3067PubMedCrossRefGoogle Scholar
  15. Carroll AM, Haines LR, Pearson TW, Brennan C, Breen EP, Porter RK (2004) Immunodetection of UCP1 in rat thymocytes. Biochem Soc Trans 32(Pt 6):1066–1067PubMedGoogle Scholar
  16. Cederberg A, Gronning LM, Ahren B, Tasken K, Carlsson P, Enerback S (2001) FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. Cell 106(5):563–573PubMedCrossRefGoogle Scholar
  17. Christensen CR, Clark PB, Morton KA (2006) Reversal of hypermetabolic brown adipose tissue in F-18 FDG PET imaging. Clin Nucl Med 31(4):193–196PubMedCrossRefGoogle Scholar
  18. Cinti S (2005) The adipose organ. Prostaglandins Leukot Essent Fatty Acids 73(1):9–15PubMedCrossRefGoogle Scholar
  19. Collins S, Kuhn CM, Petro AE, Swick AG, Chrunyk BA, Surwit RS (1996) Role of leptin in fat regulation. Nature 380(6576):677PubMedCrossRefGoogle Scholar
  20. Cunningham S, Leslie P, Hopwood D, Illingworth P, Jung RT, Nicholls DG, Peden N, Rafael J, Rial E (1985) The characterization and energetic potential of brown adipose tissue in man. Clin Sci (Lond) 69(3):343–348Google Scholar
  21. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng YH, Doria A, Kolodny GM, Kahn CR (2009) Identification and importance of brown adipose tissue in adult humans. N Engl J Med 360(15):1509–1517PubMedCrossRefGoogle Scholar
  22. Daikoku T, Shinohara Y, Shima A, Yamazaki N, Terada H (1997) Dramatic enhancement of the specific expression of the heart-type fatty acid binding protein in rat brown adipose tissue by cold exposure. FEBS Lett 410(2–3):383–386PubMedCrossRefGoogle Scholar
  23. De MR, Ricquier D, Cinti S (1998) TH-, NPY-, SP-, and CGRP-immunoreactive nerves in interscapular brown adipose tissue of adult rats acclimated at different temperatures: an immunohistochemical study. J Neurocytol 27(12):877–886CrossRefGoogle Scholar
  24. de Martinez MR, Scanlan TS, Obregon MJ (2010) The T3 receptor beta1 isoform regulates UCP1 and D2 deiodinase in rat brown adipocytes. Endocrinology 151(10):5074–5083CrossRefGoogle Scholar
  25. Enerback S (2010) Human brown adipose tissue. Cell Metab 11(4):248–252PubMedCrossRefGoogle Scholar
  26. Enerback S, Jacobsson A, Simpson EM, Guerra C, Yamashita H, Harper ME, Kozak LP (1997) Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387(6628):90–94PubMedCrossRefGoogle Scholar
  27. Forner F, Kumar C, Luber CA, Fromme T, Klingenspor M, Mann M (2009) Proteome differences between brown and white fat mitochondria reveal specialized metabolic functions. Cell Metab 10(4):324–335PubMedCrossRefGoogle Scholar
  28. Foster DO, Frydman ML (1978) Nonshivering thermogenesis in the rat. II. Measurements of blood flow with microspheres point to brown adipose tissue as the dominant site of the calorigenesis induced by noradrenaline. Can J Physiol Pharmacol 56(1):110–122PubMedCrossRefGoogle Scholar
  29. Foster DO, Frydman ML (1979) 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 57(3):257–270PubMedCrossRefGoogle Scholar
  30. Garlid KD, Orosz DE, Modriansky M, Vassanelli S, Jezek P (1996) On the mechanism of fatty acid-induced proton transport by mitochondrial uncoupling protein. J Biol Chem 271(5):2615–2620PubMedCrossRefGoogle Scholar
  31. Gesner K (1551) Conradi Gesneri medici Tigurini historiae animalium lib. I. de quadrupedibus viviparis. apud Christ. Froschoverum, Tiguri, p 1Google Scholar
  32. Giordano A, Frontini A, Castellucci M, Cinti S (2004) Presence and distribution of cholinergic nerves in rat mediastinal brown adipose tissue. J Histochem Cytochem 52(7):923–930PubMedCrossRefGoogle Scholar
  33. Golozoubova V, Hohtola E, Matthias A, Jacobsson A, Cannon B, Nedergaard J (2001) Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold. FASEB J 15(11):2048–2050PubMedGoogle Scholar
  34. Golozoubova V, Gullberg H, Matthias A, Cannon B, Vennstrom B, Nedergaard J (2004) Depressed thermogenesis but competent brown adipose tissue recruitment in mice devoid of all hormone-binding thyroid hormone receptors. Mol Endocrinol 18(2):384–401PubMedCrossRefGoogle Scholar
  35. Golozoubova V, Cannon B, Nedergaard J (2006) UCP1 is essential for adaptive adrenergic nonshivering thermogenesis. Am J Physiol Endocrinol Metab 291(2):E350–E357PubMedCrossRefGoogle Scholar
  36. Hany TF, Gharehpapagh E, Kamel EM, Buck A, Himms-Hagen J, von Schulthess GK (2002) Brown adipose tissue: a factor to consider in symmetrical tracer uptake in the neck and upper chest region. Eur J Nucl Med Mol Imaging 29(10):1393–1398PubMedCrossRefGoogle Scholar
  37. Heaton JM (1972) The distribution of brown adipose tissue in the human. J Anat 112(Pt 1):35–39PubMedGoogle Scholar
  38. Heaton GM, Wagenvoord RJ, Kemp A Jr, Nicholls DG (1978) Brown-adipose-tissue mitochondria: photoaffinity labelling of the regulatory site of energy dissipation. Eur J Biochem 82(2):515–521PubMedCrossRefGoogle Scholar
  39. Heldmaier G (1971) Zitterfreie Wärmebildung und Körpergröße bei Säugetieren. Z Vgl Physiol 73:222–248CrossRefGoogle Scholar
  40. Heldmaier G, Klingenspor M (2002) Role of photoperiod during seasonal acclimation of winter-active small mammals. In: Heldmaier G, Werner D (eds) Environmental signal processing and adaptation. Springer Verlag, Berlin, pp 251–279CrossRefGoogle Scholar
  41. Heldmaier G, Neuweiler G (2004) Vergleichende Tierphysiologie, 1st edn. Springer Verlag, Berlin, p 1Google Scholar
  42. Heldmaier G, Klaus S, Wiesinger H (1990) Seasonal adaptation of thermoregulatory heat production in small mammals. In: Bligh J, Voigt K (eds) Thermoception and thermoregulation. Springer Verlag, Berlin, pp 235–243Google Scholar
  43. Himms-Hagen J (1979) Obesity may be due to a malfunctioning of brown fat. Can Med Assoc J 121(10):1361–1364PubMedGoogle Scholar
  44. Hittelman KJ, Lindberg O, Cannon B (1969) Oxidative phosphorylation and compartmentation of fatty acid metabolism in brown fat mitochondria. Eur J Biochem 11(1):183–192PubMedCrossRefGoogle Scholar
  45. Holm C (2003) Molecular mechanisms regulating hormone-sensitive lipase and lipolysis. Biochem Soc Trans 31(Pt 6):1120–1124PubMedCrossRefGoogle Scholar
  46. Huang SG (2003) Binding of fatty acids to the uncoupling protein from brown adipose tissue mitochondria. Arch Biochem Biophys 412(1):142–146PubMedCrossRefGoogle Scholar
  47. Hughes DA, Jastroch M, Stoneking M, Klingenspor M (2009) Molecular evolution of UCP1 and the evolutionary history of mammalian non-shivering thermogenesis. BMC Evol Biol 9:4PubMedCrossRefGoogle Scholar
  48. Jastroch M, Wuertz S, Kloas W, Klingenspor M (2005) Uncoupling protein 1 in fish uncovers an ancient evolutionary history of mammalian nonshivering thermogenesis. Physiol Genomics 22(2):150–156PubMedCrossRefGoogle Scholar
  49. Jastroch M, Buckingham JA, Helwig M, Klingenspor M, Brand MD (2007) Functional characterisation of UCP1 in the common carp: uncoupling activity in liver mitochondria and cold-induced expression in the brain. J Comp Physiol B 177(7):743–752PubMedCrossRefGoogle Scholar
  50. Jastroch M, Withers KW, Taudien S, Frappell PB, Helwig M, Fromme T, Hirschberg V, Heldmaier G, McAllan BM, Firth BT, Burmester T, Platzer M, Klingenspor M (2008) Marsupial uncoupling protein 1 sheds light on the evolution of mammalian nonshivering thermogenesis. Physiol Genomics 32(2):161–169PubMedGoogle Scholar
  51. Kim SW, Her SJ, Kim SY, Shin CS (2005) Ectopic overexpression of adipogenic transcription factors induces transdifferentiation of MC3T3-E1 osteoblasts. Biochem Biophys Res Commun 327(3):811–819PubMedCrossRefGoogle Scholar
  52. Kleiber M (1967) Der Energiehaushalt von Mensch und Haustier, 1st edn. Verlag Paul Parey, BerlinGoogle Scholar
  53. Klingenspor M (2003) Cold-induced recruitment of brown adipose tissue thermogenesis. Exp Physiol 88(1):141–148PubMedCrossRefGoogle Scholar
  54. Klingenspor M, Ebbinghaus C, Hulshorst G, Stohr S, Spiegelhalter F, Haas K, Heldmaier G (1996a) Multiple regulatory steps are involved in the control of lipoprotein lipase activity in brown adipose tissue. J Lipid Res 37(8):1685–1695PubMedGoogle Scholar
  55. Klingenspor M, Ivemeyer M, Wiesinger H, Haas K, Heldmaier G, Wiesner RJ (1996b) Biogenesis of thermogenic mitochondria in brown adipose tissue of Djungarian hamsters during cold adaptation. Biochem J 316(Pt 2):607–613PubMedGoogle Scholar
  56. Konarzewski M, Diamond J (1994) Peak sustained metabolic-rate and its individual variation in cold-stressed mice. Physiol Zool 67(5):1186–1212Google Scholar
  57. Lafontan M, Berlan M (1993) Fat cell adrenergic receptors and the control of white and brown fat cell function. J Lipid Res 34(7):1057–1091PubMedGoogle Scholar
  58. Ledesma A, de Lacoba MG, Arechaga I, Rial E (2002) Modeling the transmembrane arrangement of the uncoupling protein UCP1 and topological considerations of the nucleotide-binding site. J Bioenerg Biomembr 34(6):473–486PubMedCrossRefGoogle Scholar
  59. Lee P, Greenfield JR, Ho KK, Fulham MJ (2010) A critical appraisal of the prevalence and metabolic significance of brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 299(4):E601–E606PubMedCrossRefGoogle Scholar
  60. Lin CS, Klingenberg M (1980) Isolation of the uncoupling protein from brown adipose tissue mitochondria. FEBS Lett 113(2):299–303PubMedCrossRefGoogle Scholar
  61. Lopez M, Varela L, Vazquez MJ, Rodriguez-Cuenca S, Gonzalez CR, Velagapudi VR, Morgan DA, Schoenmakers E, Agassandian K, Lage R, Martinez de Morentin PB, Tovar S, Nogueiras R, Carling D, Lelliott C, Gallego R, Oresic M, Chatterjee K, Saha AK, Rahmouni K, Dieguez C, Vidal-Puig A (2010) Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 16(9):1001–1008PubMedCrossRefGoogle Scholar
  62. Lowell BB, Spiegelman BM (2000) Towards a molecular understanding of adaptive thermogenesis. Nature 404(6778):652–660PubMedGoogle Scholar
  63. Madsen L, Pedersen LM, Lillefosse HH, Fjaere E, Bronstad I, Hao Q, Petersen RK, Hallenborg P, Ma T, De MR, Araujo P, Mercader J, Bonet ML, Hansen JB, Cannon B, Nedergaard J, Wang J, Cinti S, Voshol P, Doskeland SO, Kristiansen K (2010) UCP1 induction during recruitment of brown adipocytes in white adipose tissue is dependent on cyclooxygenase activity. PLoS One 5(6):e11391PubMedCrossRefGoogle Scholar
  64. Meyer CW, Willershauser M, Jastroch M, Rourke BC, Fromme T, Oelkrug R, Heldmaier G, Klingenspor M (2010) Adaptive thermogenesis and thermal conductance in wild-type and UCP1-KO mice. Am J Physiol Regul Integr Comp Physiol 299(5):R1396–R1406PubMedCrossRefGoogle Scholar
  65. Morrison SF (2004) Central pathways controlling brown adipose tissue thermogenesis. News Physiol Sci 19:67–74PubMedCrossRefGoogle Scholar
  66. Morrison SF, Nakamura K, Madden CJ (2008) Central control of thermogenesis in mammals. Exp Physiol 93(7):773–797PubMedCrossRefGoogle Scholar
  67. Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW (2006) Central nervous system control of food intake and body weight. Nature 443(7109):289–295PubMedCrossRefGoogle Scholar
  68. Mzilikazi N, Jastroch M, Meyer CW, Klingenspor M (2007) The molecular and biochemical basis of nonshivering thermogenesis in an African endemic mammal, Elephantulus myurus. Am J Physiol Regul Integr Comp Physiol 293(5):R2120–R2127PubMedCrossRefGoogle Scholar
  69. Nakamura K, Morrison SF (2008) A thermosensory pathway that controls body temperature. Nat Neurosci 11(1):62–71PubMedCrossRefGoogle Scholar
  70. Nautiyal KM, Dailey M, Brito N, Brito MN, Harris RB, Bartness TJ, Grill HJ (2008) Energetic responses to cold temperatures in rats lacking forebrain-caudal brain stem connections. Am J Physiol Regul Integr Comp Physiol 295(3):R789–R798PubMedCrossRefGoogle Scholar
  71. Nedergaard J, Cannon B (2010) The changed metabolic world with human brown adipose tissue: therapeutic visions. Cell Metab 11(4):268–272PubMedCrossRefGoogle Scholar
  72. Nedergaard J, Bengtsson T, Cannon B (2007) Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 293(2):E444–E452PubMedCrossRefGoogle Scholar
  73. Nicholls DG (1974) Hamster brown-adipose-tissue mitochondria. The control of respiration and the proton electrochemical potential gradient by possible physiological effectors of the proton conductance of the inner membrane. Eur J Biochem 49(3):573–583PubMedCrossRefGoogle Scholar
  74. Nicholls DG (1976) Hamster brown-adipose-tissue mitochondria. Purine nucleotide control of the ion conductance of the inner membrane, the nature of the nucleotide binding site. Eur J Biochem 62(2):223–228PubMedCrossRefGoogle Scholar
  75. Nicholls DG (2001) A history of UCP1. Biochem Soc Trans 29(Pt 6):751–755PubMedCrossRefGoogle Scholar
  76. Nicholls DG, Locke RM (1984) Thermogenic mechanisms in brown fat. Physiol Rev 64(1):1–64PubMedGoogle Scholar
  77. Parker N, Crichton PG, Vidal-Puig AJ, Brand MD (2009) Uncoupling protein-1 (UCP1) contributes to the basal proton conductance of brown adipose tissue mitochondria. J Bioenerg Biomembr 41(4):335–342PubMedCrossRefGoogle Scholar
  78. Petrovic N, Walden TB, Shabalina IG, Timmons JA, Cannon B, Nedergaard J (2010) Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. J Biol Chem 285(10):7153–7164PubMedCrossRefGoogle Scholar
  79. Puchalski W, Bockler H, Heldmaier G, Langefeld M (1987) Organ blood flow and brown adipose tissue oxygen consumption during noradrenaline-induced nonshivering thermogenesis in the Djungarian hamster. J Exp Zool 242(3):263–271PubMedCrossRefGoogle Scholar
  80. Rafael J, Ludolph HJ, Hohorst HJ (1969) Mitochondria from brown adipose tissue: uncoupling of respiratory chain phosphorylation by long fatty acids and recoupling by guanosine triphosphate. Hoppe Seylers Z Physiol Chem 350(9):1121–1131PubMedCrossRefGoogle Scholar
  81. Rafael J, Vsiansky P, Heldmaier G (1985) Seasonal adaptation of brown adipose tissue in the Djungarian Hamster. J Comp Physiol B 155(4):521–528PubMedCrossRefGoogle Scholar
  82. Rafael J, Pampel I, Wang X (1994) Effect of pH and MgCl2 on the binding of purine nucleotides to the uncoupling protein in membrane particles from brown fat mitochondria. Eur J Biochem 223(3):971–980PubMedCrossRefGoogle Scholar
  83. Rehnmark S, Nedergaard J (1989) DNA synthesis in mouse brown adipose tissue is under beta-adrenergic control. Exp Cell Res 180(2):574–579PubMedCrossRefGoogle Scholar
  84. Rial E, Zardoya R (2009) Oxidative stress, thermogenesis and evolution of uncoupling proteins. J Biol 8(6):58PubMedCrossRefGoogle Scholar
  85. Ricquier D, Kader JC (1976) Mitochondrial protein alteration in active brown fat: a soidum dodecyl sulfate-polyacrylamide gel electrophoretic study. Biochem Biophys Res Commun 73(3):577–583PubMedCrossRefGoogle Scholar
  86. Rim JS, Xue B, Gawronska-Kozak B, Kozak LP (2004) Sequestration of thermogenic transcription factors in the cytoplasm during development of brown adipose tissue. J Biol Chem 279(24):25916–25926PubMedCrossRefGoogle Scholar
  87. Robidoux J, Kumar N, Daniel KW, Moukdar F, Cyr M, Medvedev AV, Collins S (2006) Maximal beta3-adrenergic regulation of lipolysis involves Src and epidermal growth factor receptor-dependent ERK1/2 activation. J Biol Chem 281(49):37794–37802PubMedCrossRefGoogle Scholar
  88. Rolfe DF, Brand MD (1996) Contribution of mitochondrial proton leak to skeletal muscle respiration and to standard metabolic rate. Am J Physiol Cell Physiol 271(4 Pt 1):C1380–C1389Google Scholar
  89. Rosen ED, MacDougald OA (2006) Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol 7(12):885–896PubMedCrossRefGoogle Scholar
  90. Rothwell NJ, Stock MJ (1979) A role for brown adipose tissue in diet-induced thermogenesis. Nature 281(5726):31–35PubMedCrossRefGoogle Scholar
  91. Saito S, Saito CT, Shingai R (2008) Adaptive evolution of the uncoupling protein 1 gene contributed to the acquisition of novel nonshivering thermogenesis in ancestral eutherian mammals. Gene 408(1–2):37–44PubMedCrossRefGoogle Scholar
  92. 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 (2009) High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58:1526–1531PubMedCrossRefGoogle Scholar
  93. Schafer MK, Eiden LE, Weihe E (1998) Cholinergic neurons and terminal fields revealed by immunohistochemistry for the vesicular acetylcholine transporter. II. The peripheral nervous system. Neuroscience 84(2):361–376PubMedCrossRefGoogle Scholar
  94. Scholander PF, Hock R, Walters V, Johnson F, Irving L (1950a) Heat regulation in some arctic and tropical mammals and birds. Biol Bull 99(2):237–258PubMedCrossRefGoogle Scholar
  95. Scholander PF, Walters V, Hock R, Irving L (1950b) Body insulation of some arctic and tropical mammals and birds. Biol Bull 99(2):225–236PubMedCrossRefGoogle Scholar
  96. Scholander PF, Hammel HT, Andersen KL, Loyning Y (1958) Metabolic acclimation to cold in man. J Appl Physiol 12(1):1–8PubMedGoogle Scholar
  97. Seale P, Kajimura S, Yang W, Chin S, Rohas LM, Uldry M, Tavernier G, Langin D, Spiegelman BM (2007) Transcriptional control of brown fat determination by PRDM16. Cell Metab 6(1):38–54PubMedCrossRefGoogle Scholar
  98. Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, Scime A, Devarakonda S, Conroe HM, Erdjument-Bromage H, Tempst P, Rudnicki MA, Beier DR, Spiegelman BM (2008) PRDM16 controls a brown fat/skeletal muscle switch. Nature 454(7207):961–967PubMedCrossRefGoogle Scholar
  99. Shabalina IG, Jacobsson A, Cannon B, Nedergaard J (2004) Native UCP1 displays simple competitive kinetics between the regulators purine nucleotides and fatty acids. J Biol Chem 279(37):38236–38248PubMedCrossRefGoogle Scholar
  100. Shabalina IG, Ost M, Petrovic N, Vrbacky M, Nedergaard J, Cannon B (2010) Uncoupling protein-1 is not leaky. Biochim Biophys Acta 1797(6–7):773–784PubMedGoogle Scholar
  101. Silva JE (2006) Thermogenic mechanisms and their hormonal regulation. Physiol Rev 86(2):435–464PubMedCrossRefGoogle Scholar
  102. Skulachev VP (1991) Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation. FEBS Lett 294(3):158–162PubMedCrossRefGoogle Scholar
  103. Smith RE (1961) Thermogenic activity of the hibernating gland in the cold-acclimated rat. Physiologist 4:113Google Scholar
  104. Smith RE, Roberts JC, Hittelman KJ (1966) Nonphosphorylating respiration of mitochondria from brown adipose tissue of rats. Science 154(749):653–654PubMedCrossRefGoogle Scholar
  105. Soderlund V, Larsson SA, Jacobsson H (2007) Reduction of FDG uptake in brown adipose tissue in clinical patients by a single dose of propranolol. Eur J Nucl Med Mol Imaging 34(7):1018–1022PubMedCrossRefGoogle Scholar
  106. Song CK, Vaughan CH, Keen-Rhinehart E, Harris RB, Richard D, Bartness TJ (2008) Melanocortin-4 receptor mRNA expressed in sympathetic outflow neurons to brown adipose tissue: neuroanatomical and functional evidence. Am J Physiol Regul Integr Comp Physiol 295(2):R417–R428PubMedCrossRefGoogle Scholar
  107. Spiegelman BM, Flier JS (2001) Obesity and the regulation of energy balance. Cell 104(4):531–543PubMedCrossRefGoogle Scholar
  108. Ste ML, Miura GI, Marsh DJ, Yagaloff K, Palmiter RD (2000) A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors. Proc Natl Acad Sci USA 97(22):12339–12344CrossRefGoogle Scholar
  109. Stuart JA, Harper JA, Brindle KM, Jekabsons MB, Brand MD (2001) A mitochondrial uncoupling artifact can be caused by expression of uncoupling protein 1 in yeast. Biochem J 356(Pt 3):779–789PubMedCrossRefGoogle Scholar
  110. Thonberg H, Fredriksson JM, Nedergaard J, Cannon B (2002) A novel pathway for adrenergic stimulation of cAMP-response-element-binding protein (CREB) phosphorylation: mediation via alpha1-adrenoceptors and protein kinase C activation. Biochem J 364(Pt 1):73–79PubMedGoogle Scholar
  111. Thurlby PL, Trayhurn P (1980) Regional blood flow in genetically obese (ob/ob) mice. The importance of brown adipose tissue to the reduced energy expenditure on non-shivering thermogenesis. Pflugers Arch 385(3):193–201PubMedCrossRefGoogle Scholar
  112. Timmons JA, Wennmalm K, Larsson O, Walden TB, Lassmann T, Petrovic N, Hamilton DL, Gimeno RE, Wahlestedt C, Baar K, Nedergaard J, Cannon B (2007) Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages. Proc Natl Acad Sci USA 104(11):4401–4406PubMedCrossRefGoogle Scholar
  113. Traut TW (1994) Physiological concentrations of purines and pyrimidines. Mol Cell Biochem 140(1):1–22PubMedCrossRefGoogle Scholar
  114. 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 (2008) New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454(7207):1000–1004PubMedCrossRefGoogle Scholar
  115. Ukropec J, Anunciado RP, Ravussin Y, Hulver MW, Kozak LP (2006) UCP1-independent thermogenesis in white adipose tissue of cold-acclimated Ucp1−/− mice. J Biol Chem 281(42):31894–31908PubMedCrossRefGoogle Scholar
  116. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJ (2009) Cold-activated brown adipose tissue in healthy men. N Engl J Med 360(15):1500–1508PubMedCrossRefGoogle Scholar
  117. Vegiopoulos A, Muller-Decker K, Strzoda D, Schmitt I, Chichelnitskiy E, Ostertag A, Berriel DM, Rozman J, de Hrabe AM, Nusing RM, Meyer CW, Wahli W, Klingenspor M, Herzig S (2010) Cyclooxygenase-2 controls energy homeostasis in mice by de novo recruitment of brown adipocytes. Science 328(5982):1158–1161PubMedCrossRefGoogle Scholar
  118. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ, Enerback S, Nuutila P (2009) Functional brown adipose tissue in healthy adults. N Engl J Med 360(15):1518–1525PubMedCrossRefGoogle Scholar
  119. Voss-Andreae A, Murphy JG, Ellacott KL, Stuart RC, Nillni EA, Cone RD, Fan W (2007) Role of the central melanocortin circuitry in adaptive thermogenesis of brown adipose tissue. Endocrinology 148(4):1550–1560PubMedCrossRefGoogle Scholar
  120. Watanabe M, Yamamoto T, Mori C, Okada N, Yamazaki N, Kajimoto K, Kataoka M, Shinohara Y (2008) Cold-induced changes in gene expression in brown adipose tissue: implications for the activation of thermogenesis. Biol Pharm Bull 31(5):775–784PubMedCrossRefGoogle Scholar
  121. Winkler E, Klingenberg M (1994) Effect of fatty acids on H  +  transport activity of the reconstituted uncoupling protein. J Biol Chem 269(4):2508–2515PubMedGoogle Scholar
  122. Wu Z, Xie Y, Bucher NL, Farmer SR (1995) Conditional ectopic expression of C/EBP beta in NIH-3T3 cells induces PPAR gamma and stimulates adipogenesis. Genes Dev 9(19):2350–2363PubMedCrossRefGoogle Scholar
  123. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98(1):115–124PubMedCrossRefGoogle Scholar
  124. Xue B, Rim JS, Hogan JC, Coulter AA, Koza RA, Kozak LP (2007) Genetic variability affects the development of brown adipocytes in white fat but not in interscapular brown fat. J Lipid Res 48(1):41–51PubMedCrossRefGoogle Scholar
  125. Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-Gruenberger R, Riederer M, Lass A, Neuberger G, Eisenhaber F, Hermetter A, Zechner R (2004) Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 306(5700):1383–1386PubMedCrossRefGoogle Scholar
  126. Zingaretti MC, Crosta F, Vitali A, Guerrieri M, Frontini A, Cannon B, Nedergaard J, Cinti S (2009) The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J 23(9):3113–3120PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Molecular Nutritional MedicineTechnische Universität München, Else Kröner-Fresenius Center for Nutritional MedicineFreising-WeihenstephanGermany

Personalised recommendations