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Metabolic consequences of the presence or absence of the thermogenic capacity of brown adipose tissue in mice (and probably in humans)

International Journal of Obesity volume 34, pages S7–S16 (2010)Cite this article

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Abstract

Only with the development of the uncoupling protein 1 (UCP1)-ablated mouse has it become possible to strictly delineate the physiological significance of the thermogenic capacity of brown adipose tissue. Considering the presence of active brown adipose tissue in adult humans, these insights may have direct human implications. In addition to classical nonshivering thermogenesis, all adaptive adrenergic thermogeneses, including diet-induced thermogenesis, is fully dependent on brown adipocyte activity. Any weight-reducing effect of β3-adrenergic agonists is fully dependent on UCP1 activity, as is any weight-reducing effect of leptin (in excess of its effect on reduction of food intake). Consequently, in the absence of the thermogenic activity of brown adipose tissue, obesity develops spontaneously. The ability of brown adipose tissue to contribute to glucose disposal is also mainly related to thermogenic activity. However, basal metabolic rate, cold-induced thermogenesis, acute cold tolerance, fevers, nonadaptive adrenergic thermogenesis and processes such as angiogenesis in brown adipose tissue itself are not dependent on UCP1 activity. Whereas it is likely that these conclusions are also qualitatively valid for adult humans, the quantitative significance of brown adipose tissue for human metabolism—and the metabolic consequences for a single individual possessing more or less brown adipose tissue—awaits clarification.

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References

  1. Nedergaard J, Bengtsson T, Cannon B . Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol 2007; 293: E444–E452.

    CAS  Google Scholar 

  2. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB et al. Identification and importance of brown adipose tissue in adult humans. N Eng J Med 2009; 360: 1509–1517.

    Article  CAS  Google Scholar 

  3. Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 2009; 58: 1526–1531.

    Article  CAS  Google Scholar 

  4. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med 2009; 360: 1500–1508.

    Article  CAS  Google Scholar 

  5. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T et al. Functional brown adipose tissue in healthy adults. N Engl J Med 2009; 360: 1518–1525.

    Article  CAS  Google Scholar 

  6. Zingaretti MC, Crosta F, Vitali A, Guerrieri M, Frontini A, Cannon B et al. The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J 2009; 23: 3113–3120.

    Article  CAS  Google Scholar 

  7. Enerbäck S, Jacobsson A, Simpson EM, Guerra C, Yamashita H, Harper M-E et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 1997; 387: 90–94.

    Article  Google Scholar 

  8. Locke RM, Rial E, Nicholls DG . The acute regulation of mitochondrial proton conductance in cells and mitochondria from the brown fat of cold-adapted and warm-adapted guinea pigs. Eur J Biochem 1982; 129: 381–387.

    Article  CAS  Google Scholar 

  9. Matthias A, Ohlson KEB, Fredriksson JM, Jacobsson A, Nedergaard J, Cannon B . Thermogenic responses in brown-fat cells are fully UCP1-dependent: UCP2 or UCP3 do not substitute for UCP1 in adrenergically or fatty-acid induced thermogenesis. J Biol Chem 2000; 275: 25073–25081.

    Article  CAS  Google Scholar 

  10. Golozoubova V, Hohtola E, Matthias A, Jacobsson A, Cannon B, Nedergaard J . Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold. FASEB J 2001; 15: 2048–2050.

    Article  CAS  Google Scholar 

  11. Nedergaard J, Golozoubova V, Matthias A, Asadi A, Jacobsson A, Cannon B . UCP1: the only protein able to mediate adaptive non-shivering thermogenesis and metabolic inefficiency. Biochim Biophys Acta 2001; 1504: 82–106.

    Article  CAS  Google Scholar 

  12. Aydin J, Shabalina IG, Place N, Reiken S, Zhang S-J, Bellinger AM et al. Nonshivering thermogenesis protects against defective calcium handling in muscle. FASEB J 2008; 22: 3919–3924.

    Article  CAS  Google Scholar 

  13. Shabalina IG, Hoeks J, Kramarova TV, Schrauwen P, Cannon B, Nedergaard J . Cold tolerance of UCP1-ablated mice: a skeletal muscle mitochondria switch toward lipid oxidation with marked UCP3 up-regulation not associated with increased basal, fatty acid- or ROS-induced uncoupling or enhanced GDP effects. Biochim Biophys Acta 2010; 1797: 968–980.

    Article  CAS  Google Scholar 

  14. Vaanholt LM, Daan S, Schubert KA, Visser GH . Metabolism and aging: effects of cold exposure on metabolic rate, body composition, and longevity in mice. Physiol Biochem Zool 2009; 82: 314–324.

    Article  CAS  Google Scholar 

  15. Golozoubova V, Cannon B, Nedergaard J . UCP1 is essential for adaptive adrenergic nonshivering thermogenesis. Am J Physiol 2006; 291: E350–E357.

    CAS  Google Scholar 

  16. Mohell N, Connolly E, Nedergaard J . Distinction between mechanisms underlying α1- and β-adrenergic respiratory stimulation in brown fat cells. Am J Physiol 1987; 253: C301–C308.

    Article  CAS  Google Scholar 

  17. Wilcke M, Nedergaard J . 1- and β-adrenergic regulation of intracellular Ca2+ levels in brown adipocytes. Biochem Biophys Res Commun 1989; 163: 292–300.

    Article  CAS  Google Scholar 

  18. Cunningham SA, Nicholls DG . Induction of functional uncoupling protein in guinea pigs infused with noradrenaline. Biochem J 1987; 245: 485–491.

    Article  CAS  Google Scholar 

  19. Zhao J, Cannon B, Nedergaard J . 1-Adrenergic stimulation potentiates the thermogenic action of β3-adrenoceptor-generated cAMP in brown fat cells. J Biol Chem 1997; 272: 32847–32856.

    Article  CAS  Google Scholar 

  20. Zhao J, Cannon B, Nedergaard J . Thermogenesis is β3- but not β1-adrenergically mediated in rat brown fat cells, even after cold acclimation. Am J Physiol 1998; 275: R2002–R2011.

    CAS  PubMed  Google Scholar 

  21. Ohlson KBE, Mohell N, Cannon B, Lindahl SGE, Nedergaard J . Thermogenesis in brown adipocytes is inhibited by volatile anesthetic agents. A factor contributing to hypothermia in infants? Anesthesiology 1994; 81: 176–183.

    Article  CAS  Google Scholar 

  22. Dicker A, Ohlson KBE, Johnson L, Cannon B, Lindahl SGE, Nedergaard J . Halothane selectively inhibits nonshivering thermogenesis. Possible implications for thermoregulation during anesthesia of infants. Anesthesiology 1995; 82: 491–501.

    Article  CAS  Google Scholar 

  23. Ohlson KB, Lindahl SG, Cannon B, Nedergaard J . Thermogenesis inhibition in brown adipocytes is a specific property of volatile anesthetics. Anesthesiology 2003; 98: 437–448.

    Article  CAS  Google Scholar 

  24. Carlisle HJ, Stock MJ . Thermoregulatory responses to beta-adrenergic agonists at low ambient temperatures in the rat. Exp Physiol 1993; 78: 775–786.

    Article  CAS  Google Scholar 

  25. 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: 203–209.

    Article  CAS  Google Scholar 

  26. Gong DW, Monemdjou S, Gavrilova O, Leon LR, Marcus-Samuels B, Chou CJ et al. Lack of obesity and normal response to fasting and thyroid hormone in mice lacking uncoupling protein-3. J Biol Chem 2000; 275: 16251–16257.

    Article  CAS  Google Scholar 

  27. Granneman JG, Burnazi M, Zhu Z, Schwamb LA . White adipose tissue contributes to UCP1-independent thermogenesis. Am J Physiol Endocrinol Metab 2003; 285: E1230–E1236.

    Article  CAS  Google Scholar 

  28. Inokuma K-i, Okamatsu-Ogura Y, Omachi A, Matsushita Y, Kimura K, Yamashita H et al. Indispensable role of mitochondrial UCP1 for antiobesity effect of beta3-adrenergic stimulation. Am J Physiol 2006; 290: E1014–E1021.

    CAS  Google Scholar 

  29. Okamatsu-Ogura Y, Kitao N, Kimura K, Saito M . Brown fat is not involved in the febrile and thermogenic response to IL-1beta in mice. Am J Physiol 2007; 292: E1135–E1139.

    CAS  Google Scholar 

  30. Ursino MG, Vasina V, Raschi E, Crema F, De Ponti F . The beta3-adrenoceptor as a therapeutic target: current perspectives. Pharmacol Res 2009; 59: 221–234.

    Article  CAS  Google Scholar 

  31. Géloën A, Collet AJ, Guay G, Bukowiecki LJ . Adrenergic stimulation of brown adipocyte proliferation. Am J Physiol 1988; 254: C175–C182.

    Article  Google Scholar 

  32. Rehnmark S, Nedergaard J . DNA synthesis in mouse brown adipose tissue is under β-adrenergic control. Exp Cell Res 1989; 180: 574–579.

    Article  CAS  Google Scholar 

  33. Bronnikov G, Houstek J, Nedergaard J . Adrenergic, cAMP-mediated stimulation of proliferation of brown fat cells in primary culture. Mediation via β1 but not via β3 receptors. J Biol Chem 1992; 267: 2006–2013.

    CAS  PubMed  Google Scholar 

  34. Himms-Hagen J, Cui J, Danforth Jr E, Taatjes DJ, Lang SS, Waters BL et al. Effect of CL-316,243, a thermogenic beta 3-agonist, on energy balance and brown and white adipose tissues in rats. Am J Physiol 1994; 266: R1371–R1382.

    CAS  PubMed  Google Scholar 

  35. Bronnikov G, Bengtsson T, Kramarova L, Golozoubova V, Cannon B, Nedergaard J . 1 to β3 switch in control of cAMP during brown adipocyte development explains distinct β-adrenoceptor subtype mediation of proliferation and differentiation. Endocrinology 1999; 140: 4185–4197.

    Article  CAS  Google Scholar 

  36. Hoffmann C, Leitz MR, Oberdorf-Maass S, Lohse MJ, Klotz K-N . Comparative pharmacology of human beta-adrenergic receptor subtypes—characterization of stably transfected receptors in CHO cells. Naunyn-Schmiedebergs Arch Pharmacol 2004; 369: 151–159.

    Article  CAS  Google Scholar 

  37. Commins SP, Watson PM, Frampton IC, Gettys TW . Leptin selectively reduces white adipose tissue in mice via a UCP1-dependent mechanism in brown adipose tissue. Am J Physiol 2001; 280: E372–E373.

    CAS  Google Scholar 

  38. Okamatsu-Ogura Y, Uozumi A, Toda C, Kimura K, Yamashita H, Saito M . Uncoupling protein 1 contributes to fat-reducing effect of leptin. Obes Res Clin Pract 2007; 1: 233–241.

    Article  Google Scholar 

  39. Ukropec J, Anunciado RV, Ravussin Y, Kozak LP . Leptin is required for uncoupling protein-1-independent thermogenesis during cold stress. Endocrinology 2006; 147: 2468–2480.

    Article  CAS  Google Scholar 

  40. Rosenbaum M, Goldsmith R, Bloomfield D, Magnano A, Weimr L, Heymsfield S et al. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest 2005; 115: 3579–3586.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  42. Cannon B, Nedergaard J . Thermogenesis challenges the adipostat hypothesis for body-weight control. Proc Nutr Soc 2009; 64: 401–407.

    Article  Google Scholar 

  43. Kontani Y, Wang Y, Kimura K, Inokuma KI, Saito M, Suzuki-Miura T et al. UCP1 deficiency increases susceptibility to diet-induced obesity with age. Aging Cell 2005; 4: 147–155.

    Article  CAS  Google Scholar 

  44. Liu X, Rossmeisl M, McClaine J, Kozak LP . Paradoxical resistance to diet-induced obesity in UCP1-deficient mice. J Clin Invest 2003; 111: 399–407.

    Article  CAS  Google Scholar 

  45. Lee H, Mizuno A, Suzuki M, Caterina MJ . Altered thermal selection behavior in mice lacking transient receptor potential vanilloid 4. J Neurosci 2005; 25: 1304–1310.

    Article  CAS  Google Scholar 

  46. Glick Z, Raum W . Norepinephrine turnover in brown adipose tissue is stimulated by a single meal. Am J Physiol 1986; 251: R13–R17.

    CAS  PubMed  Google Scholar 

  47. Shabalina IG, Jacobsson A, Cannon B, Nedergaard J . Native UCP1 displays simple competitive kinetics between the regulators purine nucleotides and fatty acids. J Biol Chem 2004; 279: 38236–38248.

    Article  CAS  Google Scholar 

  48. Cannon B, Shabalina IG, Kramarova TV, Petrovic N, Nedergaard J . Uncoupling proteins: a role in protection against reactive oxygen species—or not? Biochim Biophys Acta 2006; 1757: 449–458.

    Article  CAS  Google Scholar 

  49. Vallerand AL, Pérusse F, Bukowiecki LJ . Stimulatory effects of cold exposure and cold acclimation on glucose uptake in rat peripheral tissues. Am J Physiol 1990; 259: R1043–R1049.

    CAS  PubMed  Google Scholar 

  50. Inokuma K, Ogura-Okamatsu Y, Toda C, Kimura K, Yamashita H, Saito M . Uncoupling protein 1 is necessary for norepinephrine-induced glucose utilization in brown adipose tissue. Diabetes 2005; 54: 1385–1391.

    Article  CAS  Google Scholar 

  51. Marette A, Bukowiecki LJ . Stimulation of glucose transport by insulin and norepinephrine in isolated rat brown adipocytes. Am J Physiol 1989; 257: C714–C721.

    Article  CAS  Google Scholar 

  52. Hutchinson D, Chernogubova E, Cannon B, Bengtsson T . Adrenoceptors, but not α-adrenoceptors, stimulate AMP-activated protein kinase in brown adipocytes independently of uncoupling protein-1. Diabetologia 2005; 48: 2386–2395.

    Article  CAS  Google Scholar 

  53. Kramarova TV, Shabalina IG, Andersson U, Westerberg R, Carlberg I, Houstek J et al. Mitochondrial ATP synthase levels in brown adipose tissue is governed by the c-Fo subunit P1 isoform. FASEB J 2008; 22: 55–63.

    Article  CAS  Google Scholar 

  54. Cannon B, Nedergaard J . The physiological role of pyruvate carboxylation in hamster brown adipose tissue. Eur J Biochem 1979; 94: 419–426.

    Article  CAS  Google Scholar 

  55. Stuart JA, Harper JA, Brindle KM, Jekabsons MB, Brand MD . A mitochondrial uncoupling artifact can be caused by expression of uncoupling protein 1 in yeast. Biochem J 2001; 356: 779–789.

    Article  CAS  Google Scholar 

  56. Griggio MA . The participation of shivering and nonshivering thermogenesis in warm and cold-acclimated rats. Comp Biochem Physiol A 1982; 73: 481–484.

    Article  CAS  Google Scholar 

  57. Rudaya AY, Steiner AA, Robbins JR, Dragic AS, Romanovsky AA . Thermoregulatory responses to lipopolysaccharide in the mouse: dependence on the dose and ambient temperature. A J Physiol 2005; 289: R1244–R1255.

    CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  59. Burysek L, Houstek J . Adrenergic stimulation of interleukin-α and interleukin-6 expression in mouse brown adipocytes. FEBS Lett 1997; 411: 83–86.

    Article  CAS  Google Scholar 

  60. Ocloo A, Shabalina IG, Nedergaard J, Brand MD . Cold-induced alterations of phospholipid fatty acyl composition in brown adipose tissue mitochondria are independent of uncoupling protein-1. Am J Physiol Integr Comp Physiol 2007; 293: R1086–R1093.

    Article  CAS  Google Scholar 

  61. Xue Y, Petrovic N, Cao R, Larsson O, Lim S, Chen S et al. Hypoxia-independent angiogenesis in adipose tissues during cold acclimation. Cell Metab 2009; 9: 99–109.

    Article  CAS  Google Scholar 

  62. Fredriksson JM, Lindquist JM, Bronnikov GE, Nedergaard J . Norepinephrine induces vascular endothelial growth factor gene expression in brown adipocytes through a β-adrenoreceptor/cAMP/protein kinase A pathway involving Src but independently of Erk1/2. J Biol Chem 2000; 275: 13802–13811.

    Article  CAS  Google Scholar 

  63. Fredriksson JM, Nikami H, Nedergaard J . Cold-induced expression of the VEGF gene in brown adipose tissue is independent of thermogenic oxygen consumption. FEBS Lett 2005; 579: 5680–5684.

    Article  CAS  Google Scholar 

  64. Esterbauer H, Oberkofler H, Liu Y, Breban D, Hell E, Krempler F et al. Uncoupling protein-1 mRNA expression in obese human subjects: the role of sequence variations at the uncoupling protein-1 gene locus. J Lipid Res 1998; 39: 834–844.

    CAS  PubMed  Google Scholar 

  65. Clement K, Ruiz J, Cassard-Doulcier AM, Bouillaud F, Ricquier D, Basdevant A et al. Additive effect of A → G (-3826) variant of the uncoupling protein gene and the Trp64Arg mutation of the beta 3-adrenergic receptor gene on weight gain in morbid obesity. Int J Obes 1996; 20: 1062–1066.

    CAS  Google Scholar 

  66. Sramkova D, Krejbichova S, Vcelak J, Vankova M, Samalikova P, Hill M et al. The UCP1 gene polymorphism A-3826G in relation to DM2 and body composition in Czech population. Exp Clin Endocrinol Diabetes 2007; 115: 303–307.

    Article  CAS  Google Scholar 

  67. Surwit RS, Wang S, Petro AE, Sanchis D, Raimbault S, Ricquier D et al. Diet-induced changes in uncoupling proteins in obesity-prone and obesity-resistant strains of mice. Proc Natl Acad Sci USA 1998; 95: 4061–4065.

    Article  CAS  Google Scholar 

  68. Rippe C, Berger K, Boiers C, Ricquier D, Erlanson-Albertsson C . Effect of high-fat diet, surrounding temperature, and enterostatin on uncoupling protein gene expression. Am J Physiol 2000; 279: E293–E300.

    CAS  Google Scholar 

  69. Nikonova L, Koza RA, Mendoza T, Chao PM, Curley JP, Kozak LP . Mesoderm-specific transcript is associated with fat mass expansion in response to a positive energy balance. FASEB J 2008; 22: 3925–3937.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank past and present members of the department for discussions and results over the years, particularly the metabolic studies of Valeria Golozoubova and Helena Feldmann. Our studies have been supported by grants from the Swedish Research Council, the Swedish Cancer Society and the European Union. We are members of the ADAPT Consortium (FP7) and the COST Action Mitofood.

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  1. Department of Physiology, The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, Stockholm, Sweden

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Cannon, B., Nedergaard, J. Metabolic consequences of the presence or absence of the thermogenic capacity of brown adipose tissue in mice (and probably in humans). Int J Obes 34 (Suppl 1), S7–S16 (2010). https://doi.org/10.1038/ijo.2010.177

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