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Translational Pharmacology and Physiology of Brown Adipose Tissue in Human Disease and Treatment

  • Christopher J. LarsonEmail author
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 251)

Abstract

Human brown adipose tissue (BAT) is experimentally modeled to better understand the biology of this important metabolic tissue, and also to enable the potential discovery and development of novel therapeutics for obesity and sequelae resulting from the persistent positive energy balance. This chapter focuses on translation into humans of findings and hypotheses generated in nonhuman models of BAT pharmacology. Given the demonstrated challenges of sustainably reducing caloric intake in modern humans, potential solutions to obesity likely lie in increasing energy expenditure. The energy-transforming activities of a single cell in any given tissue can be conceptualized as a flow of chemical energy from energy-rich substrate molecules into energy-expending, endergonic biological work processes through oxidative degradation of organic molecules ingested as nutrients. Despite the relatively tight coupling between metabolic reactions and products, some expended energy is incidentally lost as heat, and in this manner a significant fraction of the energy originally captured from the environment nonproductively transforms into heat rather than into biological work. In human and other mammalian cells, some processes are even completely uncoupled, and therefore purely energy consuming. These molecular and cellular actions sum up at the physiological level to adaptive thermogenesis, the endogenous physiology in which energy is nonproductively released as heat through uncoupling of mitochondria in brown fat and potentially skeletal muscle. Adaptive thermogenesis in mammals occurs in three forms, mostly in skeletal muscle and brown fat: shivering thermogenesis in skeletal muscle, non-shivering thermogenesis in brown fat, and diet-induced thermogenesis in brown fat. At the cellular level, the greatest energy transformations in humans and other eukaryotes occur in the mitochondria, where creating energetic inefficiency by uncoupling the conversion of energy-rich substrate molecules into ATP usable by all three major forms of biological work occurs by two primary means. Basal uncoupling occurs as a passive, general, nonspecific leak down the proton concentration gradient across the membrane in all mitochondria in the human body, a gradient driving a key step in ATP synthesis. Inducible uncoupling, which is the active conduction of protons across gradients through processes catalyzed by proteins, occurs only in select cell types including BAT. Experiments in rodents revealed UCP1 as the primary mammalian molecule accounting for the regulated, inducible uncoupling of BAT, and responsive to both cold and pharmacological stimulation. Cold stimulation of BAT has convincingly translated into humans, and older clinical observations with nonselective 2,4-DNP validate that human BAT’s participation in pharmacologically mediated, though nonselective, mitochondrial membrane decoupling can provide increased energy expenditure and corresponding body weight loss. In recent times, however, neither beta-adrenergic antagonism nor unselective sympathomimetic agonism by ephedrine and sibutramine provide convincing evidence that more BAT-selective mechanisms can impact energy balance and subsequently body weight. Although BAT activity correlates with leanness, hypothesis-driven selective β3-adrenergic agonism to activate BAT in humans has only provided robust proof of pharmacologic activation of β-adrenergic receptor signaling, limited proof of the mechanism of increased adaptive thermogenesis, and no convincing evidence that body weight loss through negative energy balance upon BAT activation can be accomplished outside of rodents. None of the five demonstrably β3 selective molecules with sufficient clinical experience to merit review provided significant weight loss in clinical trials (BRL 26830A, TAK 677, L-796568, CL 316,243, and BRL 35135). Broader conclusions regarding the human BAT therapeutic hypothesis are limited by the absence of data from most studies demonstrating specific activation of BAT thermogenesis in most studies. Additionally, more limited data sets with older or less selective β3 agonists also did not provide strong evidence of body weight effects. Encouragingly, β3-adrenergic agonists, catechins, capsinoids, and nutritional extracts, even without robust negative energy balance outcomes, all demonstrated increased total energy expenditure that in some cases could be associated with concomitant activation of BAT, though the absence of body weight loss indicates that in no cases did the magnitude of negative energy balance reach sufficient levels. Glucocorticoid receptor agonists, PPARg agonists, and thyroid hormone receptor agonists all possess defined molecular and cellular pharmacology that preclinical models predicted to be efficacious for negative energy balance and body weight loss, yet their effects on human BAT thermogenesis upon translation were inconsistent with predictions and disappointing. A few new mechanisms are nearing the stage of clinical trials and may yet provide a more quantitatively robust translation from preclinical to human experience with BAT. In conclusion, translation into humans has been demonstrated with BAT molecular pharmacology and cell biology, as well as with physiological response to cold. However, despite pharmacologically mediated, statistically significant elevation in total energy expenditure, translation into biologically meaningful negative energy balance was not achieved, as indicated by the absence of measurable loss of body weight over the duration of a clinical study.

Keywords

Adaptive thermogenesis Adrenergic Energetics Pharmacology Physiology 

References

  1. Abraham R, Zed C, Mitchell T, Parr J, Wynn V (1987) The effect of a novel beta-agonist BRL-26830A on weight and protein loss in obese patients. Int J Obes 11(3):A306Google Scholar
  2. Agrawal A, Nair N, Baghel N (2009) A novel approach for reduction of brown fat uptake on FDG PET. Br J Radiol 82(980):626–631PubMedGoogle Scholar
  3. Akase T, Shimada T, Terabayashi S, Ikeya Y, Sanada H, Aburada M (2011) Antiobesity effects of Kaempferia parviflora in spontaneously obese type II diabetic mice. J Nat Med 65(1):73–80PubMedGoogle Scholar
  4. Al-Adsani H, Hoffer LJ, Silva JE (1997) Resting energy expenditure is sensitive to small dose changes in patients on chronic thyroid hormone replacement. J Clin Endocrinol Metabol 82(4):1118–1125Google Scholar
  5. Andersen S, Kleinschmidt K, Hvingel B, Laurberg P (2012) Thyroid hyperactivity with high thyroglobulin in serum despite sufficient iodine intake in chronic cold adaptation in an Arctic Inuit hunter population. Eur J Endocrinol 166(3):433–440PubMedGoogle Scholar
  6. Arbeeny CM, Meyers DS, Hillyer DE, Bergquist KE (1995) Metabolic alterations associated with the antidiabetic effect of beta 3-adrenergic receptor agonists in obese mice. Am J Physiol Endocrinol Metab 268(4):E678–E684Google Scholar
  7. Arch JR (2008) The discovery of drugs for obesity, the metabolic effects of leptin and variable receptor pharmacology: perspectives from β 3-adrenoceptor agonists. Naunyn Schmiedeberg’s Arch Pharmacol 378(2):225Google Scholar
  8. Arch JR (2015) Horizons in the pharmacotherapy of obesity. Curr Obes Rep 4(4):451–459PubMedGoogle Scholar
  9. Arch J, Ainsworth A (1983) Thermogenic and antiobesity activity of a novel β-adrenoceptor agonist (BRL 26830A) in mice and rats. Am J Clin Nutr 38(4):549–558PubMedGoogle Scholar
  10. Arch J, Wilson S (1996) Prospects for beta 3-adrenoceptor agonists in the treatment of obesity and diabetes. Int J Obes Relat Metab Disord 20(3):191–199PubMedGoogle Scholar
  11. Arch J, Ainsworth A, Cawthorne M, Piercy V, Sennitt M, Thody V, Wilson C, Wilson S (1984a) Atypical β-adrenoceptor on brown adipocytes as target for anti-obesity drugs. Nature 309(5964):163PubMedGoogle Scholar
  12. Arch JR, Ainsworth AT, Ellis RD, Piercy V, Thody VE, Thurlby PL, Wilson C, Wilson S, Young P (1984b) Treatment of obesity with thermogenic beta-adrenoceptor agonists: studies on BRL 26830A in rodents. Int J Obes 8(Suppl 1):1–11PubMedGoogle Scholar
  13. Arner P, Hoffstedt J (1999) Adrenoceptor genes in human obesity. J Intern Med 245(6):667–672PubMedGoogle Scholar
  14. Assimacopoulos-Jeannet F, Greco-Perotto R, Terrettaz J, Meier M, Jeanrenaud B (1992) Effect of a β-adrenergic agonist on glucose transport and insulin-responsive glucose transporters (GLUT4) in brown adipose tissue of control and obese fa/fa rats. Pflugers Arch 421(1):52–58PubMedGoogle Scholar
  15. Astrup A (1986) Thermogenesis in human brown adipose tissue and skeletal muscle induced by sympathomimetic stimulation. Acta Endocrinol 112(3 Suppl):S9–S32Google Scholar
  16. Astrup A, Bulow J, Madsen J, Christensen N (1985a) Contribution of BAT and skeletal muscle to thermogenesis induced by ephedrine in man. Am J Physiol Endocrinol Metab 248(5):E507–E515Google Scholar
  17. Astrup A, Lundsgaard C, Madsen J, Christensen NJ (1985b) Enhanced thermogenic responsiveness during chronic ephedrine treatment in man. Am J Clin Nutr 42(1):83–94PubMedGoogle Scholar
  18. Atit R, Sgaier SK, Mohamed OA, Taketo MM, Dufort D, Joyner AL, Niswander L, Conlon RA (2006) β-catenin activation is necessary and sufficient to specify the dorsal dermal fate in the mouse. Dev Biol 296(1):164–176PubMedGoogle Scholar
  19. Bachman ES, Dhillon H, Zhang C-Y, Cinti S, Bianco AC, Kobilka BK, Lowell BB (2002) βAR signaling required for diet-induced thermogenesis and obesity resistance. Science 297(5582):843–845PubMedGoogle Scholar
  20. Bailey CJ, Tahrani AA, Barnett AH (2016) Future glucose-lowering drugs for type 2 diabetes. Lancet Diabetes Endocrinol 4(4):350–359Google Scholar
  21. Barbatelli G, Murano I, Madsen L, Hao Q, Jimenez M, Kristiansen K, Giacobino J, de Matteis R, 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–E1253PubMedGoogle Scholar
  22. Baskin AS, Linderman JD, Brychta RJ, McGehee S, Anflick-Chames E, Cero C, Johnson JW, O’Mara AE, Fletcher LA, Leitner BP, Duckworth CJ, Huang S, Cai H, Garraffo HM, Millo CM, Dieckmann W, Tolstikov V, Chen EY, Gao F, Narain NR, Kiebish MA, Walter PJ, Herscovitch P, Chen KY, Cypess AM (2018) Regulation of human adipose tissue activation, gallbladder size, and bile acid metabolism by a β3-adrenergic receptor agonist. Diabetes 67(10):2113–2125PubMedGoogle Scholar
  23. Bathgate B, Freebairn E, Greenland A, Reid G (1992) Functional expression of the rat brown adipose tissue uncoupling protein in Saccharomyces cerevisiae. Mol Microbiol 6(3):363–370PubMedGoogle Scholar
  24. Bianco AC, Silva JE (1988) Cold exposure rapidly induces virtual saturation of brown adipose tissue nuclear T3 receptors. Am J Physiol Endocrinol Metab 255(4):E496–E503Google Scholar
  25. Blondin DP, Labbé SM, Tingelstad HC, Noll C, Kunach M, Phoenix S, Guérin B, Turcotte ÉE, Carpentier AC, Richard D (2014) Increased brown adipose tissue oxidative capacity in cold-acclimated humans. J Clin Endocrinol Metabol 99(3):E438–E446Google Scholar
  26. Bogacka I, Xie H, Bray GA, Smith SR (2005) Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes 54(5):1392–1399PubMedGoogle Scholar
  27. Boozer C, Daly P, Homel P, Solomon J, Blanchard D, Nasser J, Strauss R, Meredith T (2002) Herbal ephedra/caffeine for weight loss: a 6-month randomized safety and efficacy trial. Int J Obes 26(5):593Google Scholar
  28. Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Boström EA, Choi JH, Long JZ (2012) A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481(7382):463PubMedPubMedCentralGoogle Scholar
  29. Bouchard C, Tremblay A, Després J-P, Nadeau A, Lupien PJ, Thériault G, Dussault J, Moorjani S, Pinault S, Fournier G (1990) The response to long-term overfeeding in identical twins. N Engl J Med 322(21):1477–1482PubMedGoogle Scholar
  30. Bray GA, Blackburn GL, Ferguson JM, Greenway FL, Jain AK, Mendel CM, Mendels J, Ryan DH, Schwartz SL, Scheinbaum ML (1999) Sibutramine produces dose-related weight loss. Obes Res 7(2):189–198PubMedGoogle Scholar
  31. Broeders EP, Vijgen GH, Havekes B, Bouvy ND, Mottaghy FM, Kars M, Schaper NC, Schrauwen P, Brans B, van Marken Lichtenbelt WD (2016) Thyroid hormone activates brown adipose tissue and increases non-shivering thermogenesis-a cohort study in a group of thyroid carcinoma patients. PLoS One 11(1):e0145049PubMedPubMedCentralGoogle Scholar
  32. Brunton L, Chabner B, Knollman B (eds) (2011) Goodman & Gilman’s the pharmacological basis of therapeutics, 12th edn. McGraw Hill, New YorkGoogle Scholar
  33. Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84(1):277–359PubMedGoogle Scholar
  34. Cannon B, Nedergaard J (2010) 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(S1):S7Google Scholar
  35. Carey AL, Kingwell BA (2013) Brown adipose tissue in humans: therapeutic potential to combat obesity. Pharmacol Ther 140(1):26–33PubMedGoogle Scholar
  36. Carey AL, Formosa MF, van Every B, Bertovic D, Eikelis N, Lambert GW, Kalff V, Duffy SJ, Cherk MH, Kingwell BA (2013) Ephedrine activates brown adipose tissue in lean but not obese humans. Diabetologia 56(1):147–155PubMedGoogle Scholar
  37. Carey AL, Vorlander C, Reddy-Luthmoodoo M, Natoli AK, Formosa MF, Bertovic DA, Anderson MJ, Duffy SJ, Kingwell BA (2014) Reduced UCP-1 content in in vitro differentiated beige/brite adipocytes derived from preadipocytes of human subcutaneous white adipose tissues in obesity. PLoS One 9(3):e91997PubMedPubMedCentralGoogle Scholar
  38. Carey AL, Pajtak R, Formosa MF, van Every B, Bertovic DA, Anderson MJ, Eikelis N, Lambert GW, Kalff V, Duffy SJ (2015) Chronic ephedrine administration decreases brown adipose tissue activity in a randomised controlled human trial: implications for obesity. Diabetologia 58(5):1045–1054PubMedGoogle Scholar
  39. Cawthorne MA, Sennitt MV, Arch JR, Smith SA (1992) BRL 35135, a potent and selective atypical beta-adrenoceptor agonist. Am J Clin Nutr 55(1 Suppl):252S–257SPubMedGoogle Scholar
  40. Cazeneuve P, Lépine R (1885) Sur les effets produits par l’ingestion et l’infusion intra-veineuse de trois colorants jaunes, derives de la houille. Compt Rend Soc Biol 101:1167–1169Google Scholar
  41. Chadwick DJ, Cardew G (2008) The origins and consequences of obesity. Wiley, HobokenGoogle Scholar
  42. Challiss RJ, Leighton B, Wllson S, Thurlby PL, Arch JR (1988) An investigation of the β-adrenoceptor that mediates metabolic responses to the novel agonist BRL28410 in rat soleus muscle. Biochem Pharmacol 37(5):947–950PubMedGoogle Scholar
  43. Chapman B, Farquhar D, Galloway S, Simpson G, Munro J (1985) The effects of BRL-26830A, a new beta-adrenoceptor agonist in refractory obesity. Int J Obes 9:230Google Scholar
  44. Chapman B, Farquahar D, Galloway S, Simpson G, Munro J (1988) The effects of a new beta-adrenoceptor agonist BRL 26830A in refractory obesity. Int J Obes 12(2):119–123PubMedGoogle Scholar
  45. Chavez AO, Molina-Carrion M, Abdul-Ghani MA, Folli F, DeFronzo RA, Tripathy D (2009) Circulating fibroblast growth factor-21 (FGF-21) is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance. Diabetes Care 32:1542–1546PubMedPubMedCentralGoogle Scholar
  46. Chen Y, Buyel JJ, Hanssen MJ, Siegel F, Pan R, Naumann J, Schell M, van der Lans A, Schlein C, Froehlich H, Heeren J, Virtanen KA, van Marken Lichtenbelt W, Pfeifer A (2016) Exosomal microRNA miR-92a concentration in serum reflects human brown fat activity. Nat Commun 7:11420PubMedPubMedCentralGoogle Scholar
  47. Christiansen E, Garby L, Sørensen TI (2005) Quantitative analysis of the energy requirements for development of obesity. J Theor Biol 234(1):99–106PubMedGoogle Scholar
  48. Clapham J, Arch J (2007) Thermogenic and metabolic antiobesity drugs: rationale and opportunities. Diabetes Obes Metab 9(3):259–275PubMedGoogle Scholar
  49. Clapham JC, Arch JR, Chapman H, Haynes A, Lister C, Moore GB, Piercy V, Carter SA, Lehner I, Smith SA, Beeley LJ, Godden RJ, Herrity N, Skehel M, Changani KK, Hockings PD, Reid DG, Squires SM, Hatcher J, Trail B, Latcham J, Rastan S, Harper AJ, Cadenas S, Buckingham JA, Brand MD, Abuin A (2000) Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean. Nature 406(6794):415–418.  https://doi.org/10.1038/35019082 CrossRefPubMedGoogle Scholar
  50. Cohade C, Osman M, Pannu HK, Wahl RL (2003a) Uptake in supraclavicular area fat (“USA-Fat”): description on (18)F-FDG PET/CT. J Nucl Med 44(2):170PubMedPubMedCentralGoogle Scholar
  51. Cohade C, Mourtzikos KA, Wahl RL (2003b) “USA-Fat”: prevalence is related to ambient outdoor temperature-evaluation with 18F-FDG PET/CT. J Nucl Med 44(8):1267–1270PubMedGoogle Scholar
  52. Colman E (2007) Dinitrophenol and obesity: an early twentieth-century regulatory dilemma. Regul Toxicol Pharmacol 48(2):115–117PubMedGoogle Scholar
  53. Commins SP, Marsh DJ, Thomas SA, Watson PM, Padgett MA, Palmiter R, Gettys TW (1999) Norepinephrine is required for leptin effects on gene expression in brown and white adipose tissue. Endocrinology 140(10):4772–4778PubMedGoogle Scholar
  54. Connacher A, Jung R, Mitchell P (1988) Weight loss in obese subjects on a restricted diet given BRL 26830A, a new atypical β adrenoceptor agonist. Br Med J (Clin Res Ed) 296(6631):1217Google Scholar
  55. Connacher A, Lakie M, Powers N, Elton R, Walsh E, Jung R (1990) Tremor and the anti-obesity drug BRL 26830A. Br J Clin Pharmacol 30(4):613–615PubMedPubMedCentralGoogle Scholar
  56. Connacher A, Bennet W, Jung R, Rennie M (1992a) Metabolic effects of three weeks administration of the beta-adrenoceptor agonist BRL 26830A. Int J Obes Relat Metab Disord 16(9):685–694PubMedGoogle Scholar
  57. Connacher AA, Bennet WM, Jung RT (1992b) Clinical studies with the β-adrenoceptor agonist BRL 26830A. Oxford University Press, OxfordGoogle Scholar
  58. Contaldo F, Scalfi L, Coltorti A, Lanzilli A (1986) Reduced cold-induced thermogenesis in familial human obesity. Klin Wochenschr 64(4):177–180PubMedGoogle Scholar
  59. Cuevas-Ramos D, Almeda-Valdes P, Gómez-Pérez FJ, Meza-Arana CE, Cruz-Bautista I, Arellano-Campos O, Navarrete-López M, Aguilar-Salinas CA (2010) Daily physical activity, fasting glucose, uric acid, and body mass index are independent factors associated with serum fibroblast growth factor 21 levels. Eur J Endocrinol 163(3):469–477PubMedGoogle Scholar
  60. Cunningham S, Leslie P, Hopwood D, Illingworth P, Jung R, Nicholls D, Peden N, Rafael J, Rial E (1985) The characterization and energetic potential of brown adipose tissue in man. Clin Sci 69(3):343–348PubMedGoogle Scholar
  61. Cutting W, Tainter M (1933) Metabolic actions of dinitrophenol: with the use of balanced and unbalanced diets. J Am Med Assoc 101(27):2099–2102Google Scholar
  62. Cutting W, Mehrtens H, Tainter M (1933) Actions and uses of dinitrophenol: promising metabolic applications. J Am Med Assoc 101(3):193–195Google Scholar
  63. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng Y-H, Doria A (2009) Identification and importance of brown adipose tissue in adult humans. N Engl J Med 360(15):1509–1517PubMedPubMedCentralGoogle Scholar
  64. Cypess AM, Chen Y-C, Sze C, Wang K, English J, Chan O, Holman AR, Tal I, Palmer MR, Kolodny GM (2012) Cold but not sympathomimetics activates human brown adipose tissue in vivo. Proc Natl Acad Sci 109(25):10001–10005PubMedGoogle Scholar
  65. Cypess AM, Weiner LS, Roberts-Toler C, Franquet Elía E, Kessler SH, Kahn PA, English J, Chatman K, Trauger SA, Doria A, Kolodny GM (2015) Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab 21(1):33–38PubMedPubMedCentralGoogle Scholar
  66. Dauncey M (1981) Influence of mild cold on 24 h energy expenditure, resting metabolism and diet-induced thermogenesis. Br J Nutr 45(2):257–267PubMedGoogle Scholar
  67. de Jesus LA, Carvalho SD, Ribeiro MO, Schneider M, Kim S-W, Harney JW, Larsen PR, Bianco AC (2001) The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. J Clin Invest 108(9):1379–1385PubMedPubMedCentralGoogle Scholar
  68. de Matteis R, Arch J, Petroni M, Ferrari D, Cinti S, Stock M (2002) Immunohistochemical identification of the β 3-adrenoceptor in intact human adipocytes and ventricular myocardium: effect of obesity and treatment with ephedrine and caffeine. Int J Obes 26(11):1442Google Scholar
  69. de Ponti F, Modini C, Gibelli G, Crema F, Frigo G (1999) Atypical β-adrenoceptors mediating relaxation in the human colon: functional evidence for β3-rather than β4-adrenoceptors. Pharmacol Res 39(5):345–348PubMedGoogle Scholar
  70. Dhar R, Stout CW, Link MS, Homoud MK, Weinstock J, Estes NM III (2005) Cardiovascular toxicities of performance-enhancing substances in sports. Mayo Clin Proc 80:1307–1315PubMedGoogle Scholar
  71. Diepvens K, Westerterp KR, Westerterp-Plantenga MS (2007) Obesity and thermogenesis related to the consumption of caffeine, ephedrine, capsaicin, and green tea. Am J Phys Regul Integr Comp Phys 292(1):R77–R85Google Scholar
  72. Digby JE, Montague CT, Sewter CP, Sanders L, Wilkison WO, O’Rahilly S, Prins JB (1998) Thiazolidinedione exposure increases the expression of uncoupling protein 1 in cultured human preadipocytes. Diabetes 47(1):138–141PubMedGoogle Scholar
  73. Dolan JA, Muenkel HA, Burns MG, Pellegrino SM, Fraser CM, Pietri F, Strosberg AD, Largis EE, Dutia MD, Bloom JD (1994) Beta-3 adrenoceptor selectivity of the dioxolane dicarboxylate phenethanolamines. J Pharmacol Exp Ther 269(3):1000–1006PubMedGoogle Scholar
  74. Dong JQ, Rossulek M, Somayaji VR, Baltrukonis D, Liang Y, Hudson K, Hernandez-Illas M, Calle RA (2015a) Pharmacokinetics and pharmacodynamics of PF-05231023, a novel long-acting FGF21 mimetic, in a first-in-human study. Br J Clin Pharmacol 80(5):1051–1063PubMedPubMedCentralGoogle Scholar
  75. Dong JQ, Rossulek M, Somayaji VR, Baltrukonis D, Liang Y, Hudson K, Hernandez-Illas M, Calle RA (2015b) Pharmacokinetics and pharmacodynamics of PF-05231023, a novel long-acting FGF21 mimetic, in a first-in-human study. Br J Clin Pharmacol 80(5):1051–1063.  https://doi.org/10.1111/bcp.12676 CrossRefPubMedPubMedCentralGoogle Scholar
  76. Doyon C, Denis RG, Baraboi ED, Samson P, Lalonde J, Deshaies Y, Richard D (2006) Effects of rimonabant (SR141716) on fasting-induced hypothalamic-pituitary-adrenal axis and neuronal activation in lean and obese Zucker rats. Diabetes 55(12):3403–3410.  https://doi.org/10.2337/db06-0504 CrossRefPubMedGoogle Scholar
  77. Dulloo A, Seydoux J, Girardier L (1991) Peripheral mechanisms of thermogenesis induced by ephedrine and caffeine in brown adipose tissue. Int J Obes 15(5):317–326PubMedGoogle Scholar
  78. Elabd C, Chiellini C, Carmona M, Galitzky J, Cochet O, Petersen R, Pénicaud L, Kristiansen K, Bouloumié A, Casteilla L (2009) Human multipotent adipose-derived stem cells differentiate into functional brown adipocytes. Stem Cells 27(11):2753–2760PubMedGoogle Scholar
  79. Elmquist JK, Maratos-Flier E, Saper CB, Flier JS (1998) Unraveling the central nervous system pathways underlying responses to leptin. Nat Neurosci 1(6):445PubMedGoogle Scholar
  80. Enerbäck S (2010) Human brown adipose tissue. Cell Metab 11(4):248–252PubMedGoogle Scholar
  81. Enerbäck S, Jacobsson A, Simpson EM, Guerra C, Yamashita H, Harper M-E, Kozak LP (1997) Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387(6628):90PubMedGoogle Scholar
  82. Feldmann HM, Golozoubova V, Cannon B, Nedergaard J (2009) UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab 9(2):203–209PubMedGoogle Scholar
  83. Ferrannini E, Galvan A, Gastaldelli A, Camastra S, Sironi A, Toschi E, Baldi S, Frascerra S, Monzani F, Antonelli A (1999) Insulin: new roles for an ancient hormone. Eur J Clin Investig 29(10):842–852Google Scholar
  84. Ferré P, Pénicaud L, Hitier Y, Meier M, Girard J (1992) Hypoglycemic effects of a beta-agonist, Ro 16-8714, in streptozotocin-diabetic rats: decreased hepatic glucose production and increased glucose utilization in oxidative muscles. Metabolism 41(2):180–183PubMedGoogle Scholar
  85. Fletcher DS, Candelore MR, Grujic D, Lowell BB, Luell S, Susulic VS, Macintyre DE (1998) Beta-3 adrenergic receptor agonists cause an increase in gastrointestinal transit time in wild-type mice, but not in mice lacking the beta-3 adrenergic receptor. J Pharmacol Exp Ther 287(2):720–724PubMedGoogle Scholar
  86. 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):257–270PubMedGoogle Scholar
  87. Gaich G, Chien JY, Fu H, Glass LC, Deeg MA, Holland WL, Kharitonenkov A, Bumol T, Schilske HK, Moller DE (2013) The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab 18(3):333–340PubMedGoogle Scholar
  88. Galgani JE, Ravussin E (2010) Effect of dihydrocapsiate on resting metabolic rate in humans. Am J Clin Nutr 92(5):1089–1093PubMedPubMedCentralGoogle Scholar
  89. Gallego-Escuredo J, Gomez-Ambrosi J, Catalan V, Domingo P, Giralt M, Frühbeck G, Villarroya F (2015) Opposite alterations in FGF21 and FGF19 levels and disturbed expression of the receptor machinery for endocrine FGFs in obese patients. Int J Obes 39(1):121Google Scholar
  90. Garcia CA, van Nostrand D, Atkins F, Acio E, Butler C, Esposito G, Kulkarni K, Majd M (2006) Reduction of brown fat 2-deoxy-2-[F-18] fluoro-D-glucose uptake by controlling environmental temperature prior to positron emission tomography scan. Mol Imaging Biol 8(1):24–29PubMedGoogle Scholar
  91. Gavrila A, Hasselgren P-O, Glasgow A, Doyle AN, Lee AJ, Fox P, Gautam S, Hennessey JV, Kolodny GM, Cypess AM (2017) Variable cold-induced brown adipose tissue response to thyroid hormone status. Thyroid 27(1):1–10PubMedPubMedCentralGoogle Scholar
  92. George A, Sinha P, Conrad G, Memon AA, Dressler EV, Wagner LM (2017) Pilot study of propranolol premedication to reduce FDG uptake in brown adipose tissue on PET scans of adolescent and young adult oncology patients. Pediatr Hematol Oncol 34(3):136–143Google Scholar
  93. Ghorbani M, Claus TH, Himms-Hagen J (1997) Hypertrophy of brown adipocytes in brown and white adipose tissues and reversal of diet-induced obesity in rats treated with a β3-adrenoceptor agonist. Biochem Pharmacol 54(1):121–131PubMedGoogle Scholar
  94. Giese J (1996) Olestra: properties, regulatory concerns, and applications. Food Technol 50(3):86Google Scholar
  95. Gimeno RE, Moller DE (2014) FGF21-based pharmacotherapy–potential utility for metabolic disorders. Trends Endocrinol Metab 25(6):303–311PubMedGoogle Scholar
  96. Gnad T, Scheibler S, von Kügelgen I, Scheele C, Kilić A, Glöde A, Hoffmann LS, Reverte-Salisa L, Horn P, Mutlu S, El-Tayeb A, Kranz M, Deuther-Conrad W, Brust P, Lidell ME, Betz MJ, Enerbäck S, Schrader J, Yegutkin GG, Müller CE, Pfeifer A (2014) Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature 516(7531):395–399PubMedGoogle Scholar
  97. Goglia F, Silvestri E, Lanni A (2002) Thyroid hormones and mitochondria. Biosci Rep 22(1):17–32PubMedGoogle Scholar
  98. 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
  99. Golozoubova V, Gullberg H, Matthias A, Cannon B, Vennström 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):384–401PubMedGoogle Scholar
  100. Golozoubova V, Cannon B, Nedergaard J (2006) UCP1 is essential for adaptive adrenergic nonshivering thermogenesis. Am J Physiol Endocrinol Metab 291(2):E350–E357PubMedGoogle Scholar
  101. Grujic D, Susulic VS, Harper ME, Himms-Hagen J, Cunningham BA, Corkey BE, Lowell BB (1997) Beta3-adrenergic receptors on white and brown adipocytes mediate beta3-selective agonist-induced effects on energy expenditure, insulin secretion, and food intake. A study using transgenic and gene knockout mice. J Biol Chem 272(28):17686–17693PubMedGoogle Scholar
  102. Guerra C, Roncero C, Porras A, Fernández M, Benito M (1996) Triiodothyronine induces the transcription of the uncoupling protein gene and stabilizes its mRNA in fetal rat brown adipocyte primary cultures. J Biol Chem 271(4):2076–2081PubMedGoogle Scholar
  103. Guerra C, Koza RA, Yamashita H, Walsh K, Kozak LP (1998) Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity. J Clin Invest 102(2):412–420PubMedPubMedCentralGoogle Scholar
  104. Gustafson B, Hammarstedt A, Hedjazifar S, Hoffmann JM, Svensson P-A, Grimsby J, Rondinone C, Smith U (2015) BMP4 and BMP antagonists regulate human white and beige adipogenesis. Diabetes 64(5):1670–1681PubMedGoogle Scholar
  105. Hafner RP, Brown GC, Brand MD (1990) Thyroid-hormone control of state-3 respiration in isolated rat liver mitochondria. Biochem J 265(3):731–734PubMedPubMedCentralGoogle Scholar
  106. Hall KD, Sacks G, Chandramohan D, Chow CC, Wang YC, Gortmaker SL, Swinburn BA (2011) Quantification of the effect of energy imbalance on bodyweight. Lancet 378(9793):826–837PubMedGoogle Scholar
  107. 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):1393–1398PubMedGoogle Scholar
  108. Harper M-E, Himms-Hagen J (2001) Mitochondrial efficiency: lessons learned from transgenic mice. Biochim Biophys Acta 1504(1):159–172PubMedGoogle Scholar
  109. Harper J, Dickinson K, Brand M (2001) Mitochondrial uncoupling as a target for drug development for the treatment of obesity. Obes Rev 2(4):255–265PubMedGoogle Scholar
  110. Harper JA, Stuart JA, Jekabsons MB, Roussel D, Brindle KM, Dickinson K, Jones RB, Brand MD (2002) Artifactual uncoupling by uncoupling protein 3 in yeast mitochondria at the concentrations found in mouse and rat skeletal-muscle mitochondria. Biochem J 361(1):49–56PubMedPubMedCentralGoogle Scholar
  111. Harper M-E, Green K, Brand MD (2008) The efficiency of cellular energy transduction and its implications for obesity. Annu Rev Nutr 28:13–33PubMedGoogle Scholar
  112. Harris RB (2000) Leptin – much more than a satiety signal. Annu Rev Nutr 20(1):45–75PubMedGoogle Scholar
  113. Heaton JM (1972) The distribution of brown adipose tissue in the human. J Anat 112(Pt 1):35PubMedPubMedCentralGoogle Scholar
  114. 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):515–521Google Scholar
  115. Himms-Hagen J (1979) Obesity may be due to a malfunctioning of brown fat. Can Med Assoc J 121(10):1361–1364PubMedPubMedCentralGoogle Scholar
  116. Himms-Hagen J (1989) Brown adipose tissue thermogenesis and obesity. Prog Lipid Res 28(2):67–115PubMedGoogle Scholar
  117. Himms-Hagen J (2004) Exercise in a pill: feasibility of energy expenditure targets. Curr Drug Targets CNS Neurol Disord 3(5):389–409PubMedGoogle Scholar
  118. Himms-Hagen J, Cui J, Danforth E Jr, Taatjes D, Lang S, Waters B, Claus T (1994) Effect of CL-316,243, a thermogenic beta 3-agonist, on energy balance and brown and white adipose tissues in rats. Am J Phys Regul Integr Comp Phys 266(4):R1371–R1382Google Scholar
  119. Hoffstedt J, Poirier O, Thorne A, Lonnqvist F, Herrmann SM, Cambien F, Arner P (1999) Polymorphism of the human [[Beta]. sub. 3]-adrenoceptor gene forms a well-conserved haplotype that is associated with moderate obesity and altered receptor function. Diabetes 48(1):203–204PubMedGoogle Scholar
  120. Hosaka T, Biggs WH, Tieu D, Boyer AD, Varki NM, Cavenee WK, Arden KC (2004) Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Proc Natl Acad Sci 101(9):2975–2980PubMedGoogle Scholar
  121. Huang Z-L, Qu W-M, Eguchi N, Chen J-F, Schwarzschild MA, Fredholm BB, Urade Y, Hayaishi O (2005) Adenosine A 2A, but not A 1, receptors mediate the arousal effect of caffeine. Nat Neurosci 8(7):858PubMedGoogle Scholar
  122. Imai T, Takakuwa R, Marchand S, Dentz E, Bornert J-M, Messaddeq N, Wendling O, Mark M, Desvergne B, Wahli W (2004) Peroxisome proliferator-activated receptor γ is required in mature white and brown adipocytes for their survival in the mouse. Proc Natl Acad Sci 101(13):4543–4547PubMedGoogle Scholar
  123. Inokuma K, Ogura-Okamatsu Y, Toda C, Kimura K, Yamashita H, Saito M (2005) Uncoupling protein 1 is necessary for norepinephrine-induced glucose utilization in brown adipose tissue. Diabetes 54(5):1385–1391PubMedGoogle Scholar
  124. Inoue N, Matsunaga Y, Satoh H, Takahashi M (2007) Enhanced energy expenditure and fat oxidation in humans with high BMI scores by the ingestion of novel and non-pungent capsaicin analogues (capsinoids). Biosci Biotechnol Biochem 71(2):380–389PubMedGoogle Scholar
  125. Isler D, Hill H-P, Meier MK (1987) Glucose metabolism in isolated brown adipocytes under β-adrenergic stimulation. Quantitative contribution of glucose to total thermogenesis. Biochem J 245(3):789–793PubMedPubMedCentralGoogle Scholar
  126. Iwami M, Mahmoud FA, Shiina T, Hirayama H, Shima T, Sugita J, Shimizu Y (2011) Extract of grains of paradise and its active principle 6-paradol trigger thermogenesis of brown adipose tissue in rats. Auton Neurosci 161(1–2):63–67PubMedGoogle Scholar
  127. Iwen KA, Backhaus J, Cassens M, Waltl M, Hedesan OC, Merkel M, Heeren J, Sina C, Rademacher L, Windjäger A (2017) Cold-induced brown adipose tissue activity alters plasma fatty acids and improves glucose metabolism in men. J Clin Endocrinol Metabol 102(11):4226–4234Google Scholar
  128. James WPT, Astrup A, Finer N, Hilsted J, Kopelman P, Rössner S, Saris WH, van Gaal LF, Group SS (2000) Effect of sibutramine on weight maintenance after weight loss: a randomised trial. Lancet 356(9248):2119–2125PubMedGoogle Scholar
  129. James WPT, Caterson ID, Coutinho W, Finer N, van Gaal LF, Maggioni AP, Torp-Pedersen C, Sharma AM, Shepherd GM, Rode RA (2010) Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med 363(10):905–917PubMedGoogle Scholar
  130. Jequier E, Munger R, Felber J (1992) Thermogenic effects of various β-adrenoceptor agonists in humans: their potential usefulness in the treatment of obesity. Oxford University Press, OxfordGoogle Scholar
  131. Jespersen NZ, Larsen TJ, Peijs L, Daugaard S, Homøe P, Loft A, de Jong J, Mathur N, Cannon B, Nedergaard J (2013) A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans. Cell Metab 17(5):798–805PubMedGoogle Scholar
  132. Jessen K, Rabøl A, Winkler K (1980) Total body and splanchnic thermogenesis in curarized man during a short exposure to cold. Acta Anaesthesiol Scand 24(4):339–344PubMedGoogle Scholar
  133. Jezek P, Orosz DE, Garlid K (1990) Reconstitution of the uncoupling protein of brown adipose tissue mitochondria. Demonstration of GDP-sensitive halide anion uniport. J Biol Chem 265(31):19296–19302PubMedGoogle Scholar
  134. Joint F (2001) Human energy requirements. Report of a Joint FAO/WHO/UNU Expert Consultation, Rome, 17–24 Oct 2001–2004Google Scholar
  135. Joy RJ (1963) Responses of cold-acclimatized men to infused norepinephrine. J Appl Physiol 18(6):1209–1212PubMedGoogle Scholar
  136. Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV, Gygi SP, Spiegelman BM (2009) Initiation of myoblast to brown fat switch by a PRDM16–C/EBP-β transcriptional complex. Nature 460(7259):1154PubMedPubMedCentralGoogle Scholar
  137. Katiyar SS, Shrago E (1989) Reconstitution of purified brown adipose tissue mitochondria uncoupling protein: demonstration of separate identity of nucleotide binding and proton translocation sites by chemical probes. Proc Natl Acad Sci 86(8):2559–2562PubMedGoogle Scholar
  138. Kawabata F, Inoue N, Yazawa S, Kawada T, Inoue K, Fushiki T (2006) 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 70(12):2824–2835PubMedGoogle Scholar
  139. Kawabata F, Inoue N, Masamoto Y, Matsumura S, Kimura W, Kadowaki M, Higashi T, Tominaga M, Inoue K, Fushiki T (2009) Non-pungent capsaicin analogs (capsinoids) increase metabolic rate and enhance thermogenesis via gastrointestinal TRPV1 in mice. Biosci Biotechnol Biochem 73(12):2690–2697PubMedGoogle Scholar
  140. Kawada T, Hagihara K-I, Iwai K (1986a) Effects of capsaicin on lipid metabolism in rats fed a high fat diet. J Nutr 116(7):1272–1278PubMedGoogle Scholar
  141. Kawada T, Watanabe T, Takaishi T, Tanaka T, Iwai K (1986b) Capsaicin-induced β-adrenergic action on energy metabolism in rats: influence of capsaicin on oxygen consumption, the respiratory quotient, and substrate utilization. Proc Soc Exp Biol Med 183(2):250–256PubMedGoogle Scholar
  142. Kern PA, Finlin BS, Zhu B, Rasouli N, McGehee RE Jr, Westgate PM, Dupont-Versteegden EE (2014) The effects of temperature and seasons on subcutaneous white adipose tissue in humans: evidence for thermogenic gene induction. J Clin Endocrinol Metabol 99(12):E2772–E2779Google Scholar
  143. Kharitonenkov A, DiMarchi R (2015) FGF21 Revolutions: recent advances illuminating FGF21 biology and medicinal properties. Trends Endocrinol Metab 26(11):608–617Google Scholar
  144. Kim S, Krynyckyi BR, Machac J, Kim CK (2008) Temporal relation between temperature change and FDG uptake in brown adipose tissue. Eur J Nucl Med Mol Imaging 35(5):984–989PubMedGoogle Scholar
  145. Kim MS, Hu HH, Aggabao PC, Geffner ME, Gilsanz V (2014) Presence of brown adipose tissue in an adolescent with severe primary hypothyroidism. J Clin Endocrinol Metabol 99(9):E1686–E1690Google Scholar
  146. Klein S, Wolfe R (1990) Whole-body lipolysis and triglyceride-fatty acid cycling in cachectic patients with esophageal cancer. J Clin Invest 86(5):1403–1408PubMedPubMedCentralGoogle Scholar
  147. Kobata K, Todo T, Yazawa S, Iwai K, Watanabe T (1998) Novel capsaicinoid-like substances, capsiate and dihydrocapsiate, from the fruits of a nonpungent cultivar, CH-19 Sweet, of pepper (Capsicum annuum L.). J Agric Food Chem 46(5):1695–1697Google Scholar
  148. Kontani Y, Wang Y, Kimura K, Inokuma KI, Saito M, Suzuki-Miura T, Wang Z, Sato Y, Mori N, Yamashita H (2005) UCP1 deficiency increases susceptibility to diet-induced obesity with age. Aging Cell 4(3):147–155PubMedGoogle Scholar
  149. Kopecky J, Clarke G, Enerbäck S, Spiegelman B, Kozak LP (1995) Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity. J Clin Invest 96(6):2914–2923PubMedPubMedCentralGoogle Scholar
  150. Krief S, Lönnqvist F, Raimbault S, Baude B, Van Spronsen A, Arner P, Strosberg AD, Ricquier D, Emorine LJ (1993) Tissue distribution of beta 3-adrenergic receptor mRNA in man. J Clin Invest 91(1):344–349PubMedPubMedCentralGoogle Scholar
  151. Kusirisin W, Srichairatanakool S, Lerttrakarnnon P, Lailerd N, Suttajit M, Jaikang C, Chaiyasut C (2009) Antioxidative activity, polyphenolic content and anti-glycation effect of some Thai medicinal plants traditionally used in diabetic patients. Med Chem 5(2):139–147PubMedGoogle Scholar
  152. Lahesmaa M, Orava J, Schalin-Jäntti C, Soinio M, Hannukainen JC, Noponen T, Kirjavainen A, Iida H, Kudomi N, Enerbäck S (2014) Hyperthyroidism increases brown fat metabolism in humans. J Clin Endocrinol Metabol 99(1):E28–E35Google Scholar
  153. Landsberg L, Saville ME, Young JB (1984) Sympathoadrenal system and regulation of thermogenesis. Am J Physiol Endocrinol Metab 247(2):E181–E189Google Scholar
  154. Larsen TM, Toubro S, van Baak MA, Gottesdiener KM, Larson P, Saris WH, Astrup A (2002) Effect of a 28-d treatment with L-796568, a novel β3-adrenergic receptor agonist, on energy expenditure and body composition in obese men. Am J Clin Nutr 76(4):780–788PubMedGoogle Scholar
  155. Lean M, James W, Jennings G, Trayhurn P (1986) Brown adipose tissue uncoupling protein content in human infants, children and adults. Clin Sci (Lond) 71(3):291–297Google Scholar
  156. Lee P, Greenfield JR, Ho KK, Fulham MJ (2010a) A critical appraisal of the prevalence and metabolic significance of brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 299(4):E601–E606PubMedGoogle Scholar
  157. Lee TA, Li Z, Zerlin A, Heber D (2010b) Effects of dihydrocapsiate on adaptive and diet-induced thermogenesis with a high protein very low calorie diet: a randomized control trial. Nutr Metab 7(1):78Google Scholar
  158. Lee P, Zhao JT, Swarbrick MM, Gracie G, Bova R, Greenfield JR, Freund J, Ho KK (2011a) High prevalence of brown adipose tissue in adult humans. J Clin Endocrinol Metabol 96(8):2450–2455Google Scholar
  159. Lee J-Y, Takahashi N, Yasubuchi M, Kim Y-I, Hashizaki H, Kim M-J, Sakamoto T, Goto T, Kawada T (2011b) Triiodothyronine induces UCP-1 expression and mitochondrial biogenesis in human adipocytes. Am J Phys Cell Phys 302(2):C463–C472Google Scholar
  160. Lehninger AH (1971) Bioenergetics. Benjamin Cummings Publishing Group, San FranciscoGoogle Scholar
  161. Leibel RL, Rosenbaum M, Hirsch J (1995) Changes in energy expenditure resulting from altered body weight. N Engl J Med 332(10):621–628PubMedGoogle Scholar
  162. Leonardsson G, Steel JH, Christian M, Pocock V, Milligan S, Bell J, So P-W, Medina-Gomez G, Vidal-Puig A, White R (2004) Nuclear receptor corepressor RIP140 regulates fat accumulation. Proc Natl Acad Sci 101(22):8437–8442PubMedGoogle Scholar
  163. Leslie WS, Hankey CR, Lean ME (2007) Weight gain as an adverse effect of some commonly prescribed drugs: a systematic review. Int J Med 100(7):395–404Google Scholar
  164. Levine JA, Eberhardt NL, Jensen MD (1999) Role of nonexercise activity thermogenesis in resistance to fat gain in humans. Science 283(5399):212–214PubMedGoogle Scholar
  165. Li B, Nolte LA, Ju J-S, Han DH, Coleman T, Holloszy JO, Semenkovich CF (2000) Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice. Nat Med 6(10):1115PubMedGoogle Scholar
  166. Li S, Li Y, Xiang L, Dong J, Liu M, Xiang G (2018) Sildenafil induces browning of subcutaneous white adipose tissue in overweight adults. Metabolism 78:106–117PubMedGoogle Scholar
  167. Lin C, Hackenberg H, Klingenberg E (1980) The uncoupling protein from brown adipose tissue mitochondria is a dimer. A hydrodynamic study. FEBS Lett 113(2):304–306PubMedGoogle Scholar
  168. Loh RKC, Formosa MF, Eikelis N, Bertovic DA, Anderson MJ, Barwood SA, Nanayakkara S, Cohen ND, La Gerche A, Reutens AT, Yap KS, Barber TW, Lambert GW, Cherk MH, Duffy SJ, Kingwell BA, Carey AL (2018) Pioglitazone reduces cold-induced brown fat glucose uptake despite induction of browning in cultured human adipocytes: a randomised, controlled trial in humans. Diabetologia 61(1):220–230PubMedGoogle Scholar
  169. López M, Varela L, Vázquez MJ, Rodríguez-Cuenca S, González CR, Velagapudi VR, Morgan DA, Schoenmakers E, Agassandian K, Lage R (2010) Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 16(9):1001PubMedPubMedCentralGoogle Scholar
  170. Lowell BB, Spiegelman BM (2000) Towards a molecular understanding of adaptive thermogenesis. Nature 404(6778):652PubMedGoogle Scholar
  171. Lowell BB, Vedrana S, Hamann A, Lawitts JA, Himms-Hagen J, Boyer BB, Kozak LP, Flier JS (1993) Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 366(6457):740PubMedGoogle Scholar
  172. Luo X-J, Peng J, Li Y-J (2011) Recent advances in the study on capsaicinoids and capsinoids. Eur J Pharmacol 650(1):1–7PubMedGoogle Scholar
  173. Luque CA, Rey JA (2002) The discovery and status of sibutramine as an anti-obesity drug. Eur J Pharmacol 440(2–3):119–128PubMedGoogle Scholar
  174. Maes HH, Neale MC, Eaves LJ (1997) Genetic and environmental factors in relative body weight and human adiposity. Behav Genet 27(4):325–351PubMedGoogle Scholar
  175. Magkos F, Kavouras SA (2005) Caffeine use in sports, pharmacokinetics in man, and cellular mechanisms of action. Crit Rev Food Sci Nutr 45(7–8):535–562PubMedGoogle Scholar
  176. Magne H, Mayer A, Plantefol L (1932) Etudes sur l’action du dinitrophenol 1-2-4 (thermol). Ann de Physiol 8:70Google Scholar
  177. Malchow-Møller A, Larsen S, Hey H, Stokholm KH, Juhl E, Quaade F (1981) Ephedrine as an anorectic: the story of the ‘Elsinore pill’. Int J Obes 5(2):183–187PubMedGoogle Scholar
  178. Manara L, Croci T, Aureggi G, Guagnini F, Maffrand J, Le Fur G, Mukenge S, Ferla G (2000) Functional assessment of β adrenoceptor subtypes in human colonic circular and longitudinal (taenia coli) smooth muscle. Gut 47(3):337–342PubMedPubMedCentralGoogle Scholar
  179. Marette A, Bukowiecki LJ (1991) Noradrenaline stimulates glucose transport in rat brown adipocytes by activating thermogenesis. Evidence that fatty acid activation of mitochondrial respiration enhances glucose transport. Biochem J 277(1):119–124PubMedPubMedCentralGoogle Scholar
  180. Masuda Y, Haramizu S, Oki K, Ohnuki K, Watanabe T, Yazawa S, Kawada T, Hashizume S-i, Fushiki T (2003) Upregulation of uncoupling proteins by oral administration of capsiate, a nonpungent capsaicin analog. J Appl Physiol 95(6):2408–2415PubMedGoogle Scholar
  181. Mathvink RJ, Tolman JS, Chitty D, Candelore MR, Cascieri MA, Colwell LF, Deng L, Feeney WP, Forrest MJ, Hom GJ (2000) Discovery of a potent, orally bioavailable β3 adrenergic receptor agonist,(R)-N-[4-[2-[[2-hydroxy-2-(3-pyridinyl) ethyl] amino] ethyl] phenyl]-4-[4-[4-(trifluoromethyl) phenyl] thiazol-2-yl] benzenesulfonamide. J Med Chem 43(21):3832–3836PubMedGoogle Scholar
  182. Matsumoto T, Miyawaki C, Ue H, Kanda T, Yoshitake Y, Moritani T (2001) Comparison of thermogenic sympathetic response to food intake between obese and non-obese young women. Obes Res 9(2):78–85.  https://doi.org/10.1038/oby.2001.10 CrossRefPubMedGoogle Scholar
  183. Matsushita M, Yoneshiro T, Aita S, Kamiya T, Kusaba N, Yamaguchi K, Takagaki K, Kameya T, Sugie H, Saito M (2015) Kaempferia parviflora extract increases whole-body energy expenditure in humans: roles of brown adipose tissue. J Nutr Sci Vitaminol 61(1):79–83PubMedGoogle Scholar
  184. Mazzucotelli A, Viguerie N, Tiraby C, Annicotte J-S, Mairal A, Klimcakova E, Lepin E, Delmar P, Dejean S, Tavernier G (2007) The transcriptional coactivator peroxisome proliferator–activated receptor (PPAR) γ coactivator-1α and the nuclear receptor PPARα control the expression of glycerol kinase and metabolism genes independently of PPARγ activation in human white adipocytes. Diabetes 56(10):2467–2475PubMedGoogle Scholar
  185. Melnyk A, Harper M, Himms-Hagen J (1997) Raising at thermoneutrality prevents obesity and hyperphagia in BAT-ablated transgenic mice. Am J Phys Regul Integr Comp Phys 272(4):R1088–R1093Google Scholar
  186. Mifflin MD, St Jeor ST, Hill LA, Scott BJ, Daugherty SA, Koh YO (1990) A new predictive equation for resting energy expenditure in healthy individuals. Am J Clin Nutr 51(2):241–247PubMedGoogle Scholar
  187. Mistry AM, Swick AG, Romsos DR (1997) Leptin rapidly lowers food intake and elevates metabolic rates in lean and Ob/Ob mice. J Nutr 127(10):2065–2072PubMedGoogle Scholar
  188. Mitchell T, Ellis R, Smith S, Robb G, Cawthorne M (1989) Effects of BRL 35135, a beta-adrenoceptor agonist with novel selectivity, on glucose tolerance and insulin sensitivity in obese subjects. Int J Obes 13(6):757–766PubMedGoogle Scholar
  189. Mitschke MM, Hoffmann LS, Gnad T, Scholz D, Kruithoff K, Mayer P, Haas B, Sassmann A, Pfeifer A, Kilić A (2013) Increased cGMP promotes healthy expansion and browning of white adipose tissue. FASEB J 27(4):1621–1630PubMedGoogle Scholar
  190. Møller N, Nielsen S, Nyholm B, Pørksen N, George K, Alberti M, Weeke J (1996) Glucose turnover, fuel oxidation and forearm substrate exchange in patients with thyrotoxicosis before and after medical treatment. Clin Endocrinol 44(4):453–459Google Scholar
  191. Morera E, de Petrocellis L, Morera L, Moriello AS, Nalli M, di Marzo V, Ortar G (2012) Synthesis and biological evaluation of [6]-gingerol analogues as transient receptor potential channel TRPV1 and TRPA1 modulators. Bioorg Med Chem Lett 22(4):1674–1677PubMedGoogle Scholar
  192. Morrison SF, Nakamura K, Madden CJ (2008) Central control of thermogenesis in mammals. Exp Physiol 93(7):773–797PubMedPubMedCentralGoogle Scholar
  193. Munro J, Chapman B, Robb G, Zed C (1987) Clinical studies with thermogenic drugs. Recent Adv Obesity ResGoogle Scholar
  194. Muzik O, Mangner TJ, Granneman JG (2012) Assessment of oxidative metabolism in brown fat using PET imaging. Front Endocrinol 3:15Google Scholar
  195. Nakamura K (2011) Central circuitries for body temperature regulation and fever. Am J Phys Regul Integr Comp Phys 301(5):R1207–R1R28Google Scholar
  196. Nakamura K, Morrison SF (2007) Central efferent pathways mediating skin cooling-evoked sympathetic thermogenesis in brown adipose tissue. Am J Phys Regul Integr Comp Phys 292(1):R127–R136Google Scholar
  197. Nedergaard J, Golozoubova V, Matthias A, Asadi A, Jacobsson A, Cannon B (2001) UCP1: the only protein able to mediate adaptive non-shivering thermogenesis and metabolic inefficiency. Biochim Biophys Acta 1504(1):82–106PubMedGoogle Scholar
  198. 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–E452PubMedGoogle Scholar
  199. Nedergaard J, Feldmann H, Cannon B (2010) Brown adipose tissue is essential for diet-induced thermogenesis: the absence of Ucp1 makes the obesity-resistant 129sv mouse obesity-prone, due to lack of adaptive adrenergic thermogenesis: T1: po. 06. Obes Rev 11:92Google Scholar
  200. Neumann RO (1902) Experimentelle beiträge zur lehre von dem täglichen nahrungsbedarf des menschen unter besonderer berück-sichtigung der notwendigen eiweissmenge. Arch Hyg (Berl) 45:1Google Scholar
  201. Newsholme E, Crabtree B (1976) Substrate cycles in metabolic regulation and in heat generation. Biochem Soc Symp 41:61–109Google Scholar
  202. 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):223–228PubMedGoogle Scholar
  203. Nicholls DG (1977) The effective proton conductance of the inner membrane of mitochondria from brown adipose tissue: dependency on proton electrochemical potential gradient. Eur J Biochem 77(2):349–356PubMedGoogle Scholar
  204. Nicholls DG (1979) Brown adipose tissue mitochondria. Biochim Biophys Acta 549(1):1–29PubMedGoogle Scholar
  205. Nicholls DG, Locke RM (1984) Thermogenic mechanisms in brown fat. Physiol Rev 64(1):1–64PubMedGoogle Scholar
  206. Nicholls DG, Rial E (1999) A history of the first uncoupling protein, UCP1. J Bioenerg Biomembr 31(5):399–406PubMedGoogle Scholar
  207. Ohnuki K, Haramizu S, Oki K, Watanabe T, Yazawa S, Fushiki T (2001a) Administration of capsiate, a non-pungent capsaicin analog, promotes energy metabolism and suppresses body fat accumulation in mice. Biosci Biotechnol Biochem 65(12):2735–2740PubMedGoogle Scholar
  208. Ohnuki K, Niwa S, Maeda S, Inoue N, Yazawa S, Fushiki T (2001b) CH-19 sweet, a non-pungent cultivar of red pepper, increased body temperature and oxygen consumption in humans. Biosci Biotechnol Biochem 65(9):2033–2036PubMedGoogle Scholar
  209. Ono K, Tsukamoto-Yasui M, Hara-Kimura Y, Inoue N, Nogusa Y, Okabe Y, Nagashima K, Kato F (2010) Intragastric administration of capsiate, a transient receptor potential channel agonist, triggers thermogenic sympathetic responses. J Appl Physiol 110(3):789–798PubMedGoogle Scholar
  210. Ooijen AMC, Westerterp KR, Wouters L, Schoffelen PF, van Steenhoven AA, van Lichtenbelt WDM (2006) Heat production and body temperature during cooling and rewarming in overweight and lean men. Obesity 14(11):1914–1920Google Scholar
  211. Orava J, Nuutila P, Lidell ME, Oikonen V, Noponen T, Viljanen T, Scheinin M, Taittonen M, Niemi T, Enerbäck S (2011) Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metab 14(2):272–279Google Scholar
  212. Ouellet V, Routhier-Labadie A, Bellemare W, Lakhal-Chaieb L, Turcotte E, Carpentier AC, Richard D (2011) 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 Metabol 96(1):192–199Google Scholar
  213. Ouellet V, Labbé SM, Blondin DP, Phoenix S, Guérin B, Haman F, Turcotte EE, Richard D, Carpentier AC (2012) Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J Clin Invest 122(2):545–552PubMedPubMedCentralGoogle Scholar
  214. Padwal RS, Majumdar SR (2007) Drug treatments for obesity: orlistat, sibutramine, and rimonabant. Lancet 369(9555):71–77PubMedGoogle Scholar
  215. Pagotto U, Vanuzzo D, Vicennati V, Pasquali R (2008) Pharmacological therapy of obesity. G Ital Cardiol (Rome) 9(4 Suppl 1):83s–93sGoogle Scholar
  216. Parascandola J (1974) Dinitrophenol and bioenergetics: an historical perspective. Mol Cell Biochem 5(1–2):69–77PubMedGoogle Scholar
  217. Parysow O, Mollerach AM, Jager V, Racioppi S, San Roman J, Gerbaudo VH (2007) Low-dose oral propranolol could reduce brown adipose tissue F-18 FDG uptake in patients undergoing PET scans. Clin Nucl Med 32(5):351–357PubMedGoogle Scholar
  218. Pasquali R, Baraldi G, Cesari M, Melchionda N, Zamboni M, Stefanini C, Raitano A (1985) A controlled trial using ephedrine in the treatment of obesity. Int J Obes 9(2):93–98PubMedGoogle Scholar
  219. Pecqueur C, Alves-Guerra M-C, Gelly C, Lévi-Meyrueis C, Couplan E, Collins S, Ricquier D, Bouillaud F, Miroux B (2000) Uncoupling protein 2: in vivo distribution, induction upon oxidative stress and evidence for translational regulation. J Biol Chem 276:8705–8712PubMedGoogle Scholar
  220. Peterson CM, Lecoultre V, Frost EA, Simmons J, Redman LM, Ravussin E (2016) The thermogenic responses to overfeeding and cold are differentially regulated. Obesity (Silver Spring) 24(1):96–101.  https://doi.org/10.1002/oby.21233 CrossRefGoogle Scholar
  221. Petrovic N, Walden TB, Shabalina IG, Timmons JA, Cannon B, Nedergaard J (2010) Chronic peroxisome proliferator-activated receptor γ (PPARγ) 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):7153–7164PubMedGoogle Scholar
  222. Poehlman ET (1989) A review: exercise and its influence on resting energy metabolism in man. Med Sci Sports Exerc 21(5):515–525PubMedGoogle Scholar
  223. Ramage LE, Akyol M, Fletcher AM, Forsythe J, Nixon M, Carter RN, van Beek EJ, Morton NM, Walker BR, Stimson RH (2016) Glucocorticoids acutely increase brown adipose tissue activity in humans, revealing species-specific differences in UCP-1 regulation. Cell Metab 24(1):130–141PubMedPubMedCentralGoogle Scholar
  224. Randle P, Garland P, Hales C, Newsholme E (1963) The glucose fatty-acid cycle its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 281(7285):785–789Google Scholar
  225. Ravussin E, Kozak L (2009) Have we entered the brown adipose tissue renaissance? Obes Rev 10(3):265–268PubMedPubMedCentralGoogle Scholar
  226. Ravussin E, Lillioja S, Knowler WC, Christin L, Freymond D, Abbott WG, Boyce V, Howard BV, Bogardus C (1988) Reduced rate of energy expenditure as a risk factor for body-weight gain. N Engl J Med 318(8):467–472PubMedGoogle Scholar
  227. Ravussin Y, Xiao C, Gavrilova O, Reitman ML (2014) Effect of intermittent cold exposure on brown fat activation, obesity, and energy homeostasis in mice. PLoS One 9(1):e85876PubMedPubMedCentralGoogle Scholar
  228. Redman LM, de Jonge L, Fang X, Gamlin B, Recker D, Greenway FL, Smith SR, Ravussin E (2006) Lack of an effect of a novel β3-adrenoceptor agonist, TAK-677, on energy metabolism in obese individuals: a double-blind, placebo-controlled randomized study. J Clin Endocrinol Metabol 92(2):527–531Google Scholar
  229. Redman LM, Heilbronn LK, Martin CK, de Jonge L, Williamson DA, Delany JP, Ravussin E (2009) Metabolic and behavioral compensations in response to caloric restriction: implications for the maintenance of weight loss. PLoS One 4(2):e4377PubMedPubMedCentralGoogle Scholar
  230. Reitman ML (2013) FGF21 mimetic shows therapeutic promise. Cell Metab 18(3):307–309PubMedPubMedCentralGoogle Scholar
  231. Richard D, Picard F (2011) Brown fat biology and thermogenesis. Front Biosci 16:1233–1260Google Scholar
  232. Ricquier D, Bouillaud F (2000) The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP. Biochem J 345(2):161–179PubMedPubMedCentralGoogle Scholar
  233. Riera C, Menozzi-Smarrito C, Affolter M, Michlig S, Munari C, Robert F, Vogel H, Simon S, Le Coutre J (2009) Compounds from Sichuan and Melegueta peppers activate, covalently and non-covalently, TRPA1 and TRPV1 channels. Br J Pharmacol 157(8):1398–1409PubMedPubMedCentralGoogle Scholar
  234. Roberts-Toler C, O’Neill BT, Cypess AM (2015) Diet-induced obesity causes insulin resistance in mouse brown adipose tissue. Obesity (Silver Spring) 23(9):1765–1770Google Scholar
  235. Robidoux J, Martin TL, Collins S (2004) β-Adrenergic receptors and regulation of energy expenditure: a family affair. Annu Rev Pharmacol Toxicol 44:297–323PubMedGoogle Scholar
  236. Rodgers RJ, Tschöp MH, Wilding JP (2012) Anti-obesity drugs: past, present and future. Dis Model Mech 5(5):621–626PubMedPubMedCentralGoogle Scholar
  237. Rolfe D, Brand MD (1996) Contribution of mitochondrial proton leak to skeletal muscle respiration and to standard metabolic rate. Am J Physiol Cell Physiol 271(4):C1380–C1389Google Scholar
  238. Rolfe D, Brown GC (1997) Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol Rev 77(3):731–758PubMedGoogle Scholar
  239. Rolfe DF, Hulbert A, Brand MD (1994) Characteristics of mitochondrial proton leak and control of oxidative phosphorylation in the major oxygen-consuming tissues of the rat. Biochim Biophys Acta 1188(3):405–416PubMedGoogle Scholar
  240. Rolfe DF, Newman JM, Buckingham JA, Clark MG, Brand MD (1999) Contribution of mitochondrial proton leak to respiration rate in working skeletal muscle and liver and to SMR. Am J Physiol Cell Physiol 276(3):C692–C699Google Scholar
  241. Rosenbaum M, Goldsmith R, Bloomfield D, Magnano A, Weimer L, Heymsfield S, Gallagher D, Mayer L, Murphy E, Leibel RL (2005) Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest 115(12):3579–3586PubMedPubMedCentralGoogle Scholar
  242. Rothwell NJ, Stock MJ (1979a) A role for brown adipose tissue in diet-induced thermogenesis. Nature 281(5726):31PubMedGoogle Scholar
  243. Rothwell NJ, Stock MJ (1979b) Regulation of energy balance in two models of reversible obesity in the rat. J Comp Physiol Psychol 93(6):1024PubMedGoogle Scholar
  244. Rothwell N, Stock M (1983) Luxuskonsumption, diet-induced thermogenesis and brown fat: the case in favour. Clin Sci 64(1):19–23PubMedGoogle Scholar
  245. Rothwell N, Stock M (1987) Influence of clenbuterol on energy balance, thermogenesis and body composition in lean and genetically obese Zucker rats. Int J Obes 11(6):641–647PubMedGoogle Scholar
  246. Rousseau C, Bourbouloux E, Campion L, Fleury N, Bridji B, Chatal J, Resche I, Campone M (2006) Brown fat in breast cancer patients: analysis of serial 18F-FDG PET/CT scans. Eur J Nucl Med Mol Imaging 33(7):785–791PubMedGoogle Scholar
  247. Ruan CC, Kong LR, Chen XH, Ma Y, Pan XX, Zhang ZB, Gao PJ (2018) A2A receptor activation attenuates hypertensive cardiac remodeling via promoting brown adipose tissue-derived FGF21. Cell Metab 28(3):476–489PubMedGoogle Scholar
  248. Rujjanawate C, Kanjanapothi D, Amornlerdpison D, Pojanagaroon S (2005) Anti-gastric ulcer effect of Kaempferia parviflora. J Ethnopharmacol 102(1):120–122PubMedGoogle Scholar
  249. Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J, Iwanaga T, Miyagawa M, Kameya T, Nakada K (2009) High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58:1526–1531.  https://doi.org/10.2337/db09-0530 CrossRefPubMedPubMedCentralGoogle Scholar
  250. Schöder H, Larson SM, Yeung HW (2004) PET/CT in oncology: integration into clinical management of lymphoma, melanoma, and gastrointestinal malignancies. J Nucl Med 45(1 suppl):72S–81SPubMedGoogle Scholar
  251. Scotney H, Symonds ME, Law J, Budge H, Sharkey D, Manolopoulos KN (2017) Glucocorticoids modulate human brown adipose tissue thermogenesis in vivo. Metabolism 70:125–132PubMedPubMedCentralGoogle Scholar
  252. Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, Scime A, Devarakonda S, Conroe HM, Erdjument-Bromage H (2008) PRDM16 controls a brown fat/skeletal muscle switch. Nature 454(7207):961PubMedPubMedCentralGoogle Scholar
  253. Shannon JR, Gottesdiener K, Jordan J, Kong C, Flattery S, Larson PJ, Candelore MR, Gertz B, Robertson D, Ming S (1999) Acute effect of ephedrine on 24-h energy balance. Clin Sci 96(5):483–491PubMedGoogle Scholar
  254. Shaw WN, Schmiegel KK, Yen TT, Toomey RE, Meyers DB, Mills J (1981) LY79771: a novel compound for weight control. Life Sci 29(20):2091–2101PubMedGoogle Scholar
  255. Shekelle PG, Hardy ML, Morton SC, Maglione M, Mojica WA, Suttorp MJ, Rhodes SL, Jungvig L, Gagné J (2003) Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis. JAMA 289(12):1537–1545PubMedGoogle Scholar
  256. Shimada T, Horikawa T, Ikeya Y, Matsuo H, Kinoshita K, Taguchi T, Ichinose K, Takahashi K, Aburada M (2011) Preventive effect of Kaempferia parviflora ethyl acetate extract and its major components polymethoxyflavonoid on metabolic diseases. Fitoterapia 82(8):1272–1278PubMedGoogle Scholar
  257. Shintaku K, Uchida K, Suzuki Y, Zhou Y, Fushiki T, Watanabe T, Yazawa S, Tominaga M (2012) Activation of transient receptor potential A1 by a non-pungent capsaicin-like compound, capsiate. Br J Pharmacol 165(5):1476–1486PubMedPubMedCentralGoogle Scholar
  258. Sidossis LS, Porter C, Saraf MK, Børsheim E, Radhakrishnan RS, Chao T, Ali A, Chondronikola M, Mlcak R, Finnerty CC (2015) Browning of subcutaneous white adipose tissue in humans after severe adrenergic stress. Cell Metab 22(2):219–227PubMedPubMedCentralGoogle Scholar
  259. Silva JE (2006) Thermogenic mechanisms and their hormonal regulation. Physiol Rev 86(2):435–464PubMedGoogle Scholar
  260. Silva JE, Bianco SD (2008) Thyroid–adrenergic interactions: physiological and clinical implications. Thyroid 18(2):157–165PubMedGoogle Scholar
  261. Sjostrom L, Schutz Y, Gudinchet F, Hegnell L, Pittet P, Jequier E (1983) Epinephrine sensitivity with respect to metabolic rate and other variables in women. Am J Physiol Endocrinol Metab 245(5):E431–E442Google Scholar
  262. Sjöström L, Rissanen A, Andersen T, Boldrin M, Golay A, Koppeschaar HP, Krempf M, Group EMOS (1998) Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. Lancet 352(9123):167–172PubMedGoogle Scholar
  263. Skarulis MC, Celi FS, Mueller E, Zemskova M, Malek R, Hugendubler L, Cochran C, Solomon J, Chen C, Gorden P (2010) Thyroid hormone induced brown adipose tissue and amelioration of diabetes in a patient with extreme insulin resistance. J Clin Endocrinol Metabol 95(1):256–262Google Scholar
  264. Smith S, Cawthorne M, Fay L, McCullough D, Mitchell T (1987) Effect of a novel-adrenoceptor agonist on insulin sensitivity in lean healthy male volunteers. Diabetes 36(Suppl 1):15AGoogle Scholar
  265. Smith S, Zed C, McCullough D, Harris G, Cawthorne M (1989) Thermogenic activity in man of BRL 35135: a potent and selective atypical β-adrenoceptor agonist. Int J Obes 13(suppl 1):33Google Scholar
  266. Snitker S, Fujishima Y, Shen H, Ott S, Pi-Sunyer X, Furuhata Y, Sato H, Takahashi M (2008) Effects of novel capsinoid treatment on fatness and energy metabolism in humans: possible pharmacogenetic implications. Am J Clin Nutr 89(1):45–50PubMedPubMedCentralGoogle Scholar
  267. Söderlund 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):1018–1022PubMedGoogle Scholar
  268. Stanford KI, Middelbeek RJ, Townsend KL, An D, Nygaard EB, Hitchcox KM, Markan KR, Nakano K, Hirshman MF, Tseng Y-H (2012) Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest 123(1):215–223PubMedPubMedCentralGoogle Scholar
  269. Stowell KM (2008) Malignant hyperthermia: a pharmacogenetic disorder. Pharmacogenomics 9:1657–1672PubMedGoogle Scholar
  270. Strieleman PJ, Schalinske KL, Shrago E (1985) Fatty acid activation of the reconstituted brown adipose tissue mitochondria uncoupling protein. J Biol Chem 260(25):13402–13405PubMedGoogle Scholar
  271. Strosberg AD, Pietri-Rouxel F (1996) Function and regulation of the β3-adrenoceptor. Trends Pharmacol Sci 17(10):373–381PubMedGoogle Scholar
  272. Sugita J, Yoneshiro T, Hatano T, Aita S, Ikemoto T, Uchiwa H, Iwanaga T, Kameya T, Kawai Y, Saito M (2013) Grains of paradise (Aframomum melegueta) extract activates brown adipose tissue and increases whole-body energy expenditure in men. Br J Nutr 110(4):733–738PubMedGoogle Scholar
  273. Sugita J, Yoneshiro T, Sugishima Y, Ikemoto T, Uchiwa H, Suzuki I, Saito M (2014) Daily ingestion of grains of paradise (Aframomum melegueta) extract increases whole-body energy expenditure and decreases visceral fat in humans. J Nutr Sci Vitaminol 60(1):22–27PubMedGoogle Scholar
  274. Yoo HS, Qiao L, Bosco C, Leong L-H, Lytle N, Feng G-S, Chi N-W, Shao J (2014) Intermittent cold exposure enhances fat accumulation in mice. PLoS One 9(5):e96432PubMedPubMedCentralGoogle Scholar
  275. Tai T-AC, Jennermann C, Brown KK, Oliver BB, MacGinnitie MA, Wilkison WO, Brown HR, Lehmann JM, Kliewer SA, Morris DC (1996) Activation of the nuclear receptor peroxisome proliferator-activated receptor γ promotes brown adipocyte differentiation. J Biol Chem 271(47):29909–29914PubMedGoogle Scholar
  276. Tainter ML, Cutting WC, Stockton A (1934) Use of dinitrophenol in nutritional disorders: a critical survey of clinical results. Am J Public Health Nat Health 24(10):1045–1053Google Scholar
  277. Tajino K, Hosokawa H, Maegawa S, Matsumura K, Dhaka A, Kobayashi S (2011) Cooling-sensitive TRPM8 is thermostat of skin temperature against cooling. PLoS One 6(3):e17504PubMedPubMedCentralGoogle Scholar
  278. Talukdar S, Zhou Y, Li D, Rossulek M, Dong J, Somayaji V, Weng Y, Clark R, Lanba A, Owen BM, Brenner MB, Trimmer JK, Gropp KE, Chabot JR, Erion DM, Rolph TP, Goodwin B, Calle RA (2016) A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab 23(3):427–440.  https://doi.org/10.1016/j.cmet.2016.02.001 CrossRefPubMedGoogle Scholar
  279. Tata J, Ernster L, Lindberg O (1962) Control of basal metabolic rate by thyroid hormones and cellular function. Nature 193(4820):1058–1060PubMedGoogle Scholar
  280. Tatsumi M, Engles JM, Ishimori T, Cohade C, Wahl RL (2004) Intense 18F-FDG uptake in brown fat can be reduced pharmacologically. J Nucl Med 45(7):1189–1193PubMedGoogle Scholar
  281. Timmons JA, Wennmalm K, Larsson O, Walden TB, Lassmann T, Petrovic N, Hamilton DL, Gimeno RE, Wahlestedt C, Baar K (2007) Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages. Proc Natl Acad Sci 104(11):4401–4406PubMedGoogle Scholar
  282. Toubro S, Astrup A, Hardmann M (1993) A double-blind randomized 14 day trial of the effect of the β-3 agonist ICI D-7114 on 24 h energy expenditure and substrate oxidation in adipose patients. Int J Obes 17:S73Google Scholar
  283. Trayhurn P, Thurlby P, James W (1977) Thermogenic defect in pre-obese Ob/Ob mice. Nature 266(5597):60PubMedGoogle Scholar
  284. Trayhurn P, Goodbody AE, James WP (1982) A role for brown adipose tissue in the genesis of obesity? Studies on experimental animals. Proc Nutr Soc 41(2):127–131PubMedGoogle Scholar
  285. Tseng Y-H, Cypess AM, Kahn CR (2010) Cellular bioenergetics as a target for obesity therapy. Nat Rev Drug Discov 9(6):465PubMedPubMedCentralGoogle Scholar
  286. Uslu L, Donig J, Link M, Rosenberg J, Quon A, Daldrup-Link HE (2015) Value of 18F-FDG PET and PET/CT for evaluation of pediatric malignancies. J Nucl Med 56:274–286PubMedGoogle Scholar
  287. Vallerand AL, Perusse F, Bukowiecki LJ (1987) Cold exposure potentiates the effect of insulin on in vivo glucose uptake. Am J Physiol Endocrinol Metab 253(2):E179–E186Google Scholar
  288. van Baak MA, Hul GB, Toubro S, Astrup A, Gottesdiener KM, DeSmet M, Saris WH (2002) Acute effect of L-796568, a novel β3-adrenergic receptor agonist, on energy expenditure in obese men. Clin Pharmacol Ther 71(4):272–279PubMedGoogle Scholar
  289. van der Lans AA, Hoeks J, Brans B, Vijgen GH, Visser MG, Vosselman MJ, Hansen J, Jörgensen JA, Wu J, Mottaghy FM (2013) Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. J Clin Invest 123(8):3395–3403PubMedPubMedCentralGoogle Scholar
  290. van Marken Lichtenbelt WD, Schrauwen P (2011) Implications of nonshivering thermogenesis for energy balance regulation in humans. Am J Phys Regul Integr Comp Phys 301(2):R285–R296Google Scholar
  291. van Marken Lichtenbelt WD, Schrauwen P, van de Kerckhove S, Westerterp-Plantenga MS (2002) Individual variation in body temperature and energy expenditure in response to mild cold. Am J Physiol Endocrinol Metab 282(5):E1077–E1083PubMedGoogle Scholar
  292. 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):1500–1508PubMedPubMedCentralGoogle Scholar
  293. van Marken Lichtenbelt W, Kingma B, van der Lans A, Schellen L (2014) Cold exposure – an approach to increasing energy expenditure in humans. Trends Endocrinol Metab 25(4):165–167Google Scholar
  294. Vijgen GH, Bouvy ND, Teule GJ, Brans B, Schrauwen P, van Marken Lichtenbelt WD (2011) Brown adipose tissue in morbidly obese subjects. PLoS One 6(2):e17247PubMedPubMedCentralGoogle Scholar
  295. Villarroya J, Cereijo R, Villarroya F (2013) An endocrine role for brown adipose tissue? Am J Physiol Endocrinol Metab 305(5):E567–E572PubMedGoogle Scholar
  296. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto N-J, Enerbäck S (2009) Functional brown adipose tissue in healthy adults. N Engl J Med 360(15):1518–1525PubMedPubMedCentralGoogle Scholar
  297. Vosselman MJ, van der Lans AA, Brans B, Wierts R, van Baak MA, Schrauwen P, van Marken Lichtenbelt WD (2012) Systemic β-adrenergic stimulation of thermogenesis is not accompanied by brown adipose tissue activity in humans. Diabetes 61:3106–3113PubMedPubMedCentralGoogle Scholar
  298. Waldén TB (2010) Regulatory factors that reveal three distinct adipocytes: the brown, the white and the brite. The Wenner-Gren Institute, Stockholm University, StockholmGoogle Scholar
  299. Weyer C, Tataranni PA, Snitker S, Danforth E, Ravussin E (1998) Increase in insulin action and fat oxidation after treatment with CL 316,243, a highly selective beta3-adrenoceptor agonist in humans. Diabetes 47(10):1555–1561PubMedGoogle Scholar
  300. Weyer C, Bogardus C, Mott DM, Pratley RE (1999a) The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 104(6):787–794PubMedPubMedCentralGoogle Scholar
  301. Weyer C, Gautier J, Danforth E Jr (1999b) Development of beta 3-adrenoceptor agonists for the treatment of obesity and diabetes an update. Diabetes Metab 25:11–21PubMedGoogle Scholar
  302. Wheeldon N, McDevitt D, Lipworth B (1993) Do β3-adrenoceptors mediate metabolic responses to isoprenaline. Int J Med 86(9):595–600Google Scholar
  303. Wheeldon N, McDevitt D, McFarlane L, Lipworth B (1994) β-Adrenoceptor subtypes mediating the metabolic effects of BRL 35135 in man. Clin Sci 86(3):331–337PubMedGoogle Scholar
  304. Wijers SL, Saris WH, van Marken Lichtenbelt WD (2007) Individual thermogenic responses to mild cold and overfeeding are closely related. J Clin Endocrinol Metabol 92(11):4299–4305Google Scholar
  305. Wijers SL, Schrauwen P, Saris WH, van Marken Lichtenbelt WD (2008) Human skeletal muscle mitochondrial uncoupling is associated with cold induced adaptive thermogenesis. PLoS One 3(3):e1777PubMedPubMedCentralGoogle Scholar
  306. Wijers SL, Saris WH, Lichtenbelt WDM (2010) Cold-induced adaptive thermogenesis in lean and obese. Obesity 18(6):1092–1099PubMedGoogle Scholar
  307. Wijers SL, Schrauwen P, van Baak MA, Saris WH, van Marken Lichtenbelt WD (2011) β-Adrenergic receptor blockade does not inhibit cold-induced thermogenesis in humans: possible involvement of brown adipose tissue. J Clin Endocrinol Metabol 96(4):E598–E605Google Scholar
  308. Wilson S, Thurlby PL, Arch JR (1987) Substrate supply for thermogenesis induced by the beta-adrenoceptor agonist BRL 26830A. Can J Physiol Pharmacol 65(2):113–119PubMedGoogle Scholar
  309. Wolfe RR, Herndon DN, Jahoor F, Miyoshi H, Wolfe M (1987) Effect of severe burn injury on substrate cycling by glucose and fatty acids. N Engl J Med 317(7):403–408PubMedGoogle Scholar
  310. Wolfe RR, Klein S, Carraro F, Weber J-M (1990) Role of triglyceride-fatty acid cycle in controlling fat metabolism in humans during and after exercise. Am J Physiol Endocrinol Metab 258(2):E382–E389Google Scholar
  311. Yang X, Enerbäck S, Smith U (2003) Reduced expression of FOXC2 and brown adipogenic genes in human subjects with insulin resistance. Obes Res 11(10):1182–1191PubMedGoogle Scholar
  312. Yazawa S, Suetom N, Okamoto K, Namiki T (1989) Content of capsaicinoids and capsaicinoid-like substances in fruit of pepper (Capsicum annuum L.) hybrids made with ‘CH-19 sweet’ as a parent. J Jpn Soc Hortic Sci 58(3):601–607Google Scholar
  313. Ye X, Qi J, Ren G, Xu P, Wu Y, Zhu S, Yu D, Li S, Wu Q, Muhi RL (2015) Long-lasting anti-diabetic efficacy of PEGylated FGF-21 and liraglutide in treatment of type 2 diabetic mice. Endocrine 49(3):683–692PubMedGoogle Scholar
  314. Yen T (1984) The antiobesity and metabolic activities of LY79771 in obese and normal mice. Int J Obes 8(1):69–78PubMedGoogle Scholar
  315. Yen T, McKee M, Stamm N (1984) Thermogenesis and weight control. Int J Obes 8:65–78PubMedGoogle Scholar
  316. Yen T, Fuller R, Hemrick-Luecke S, Dininger N (1988) Effects of LY104119, a thermogenic weight-reducing compound, on norepinephrine concentrations and turnover in obese and lean mice. Int J Obes 12(1):59–67PubMedGoogle Scholar
  317. Yenjai C, Prasanphen K, Daodee S, Wongpanich V, Kittakoop P (2004) Bioactive flavonoids from Kaempferia parviflora. Fitoterapia 75(1):89–92PubMedGoogle Scholar
  318. Yoneshiro T, Saito M (2013) Transient receptor potential activated brown fat thermogenesis as a target of food ingredients for obesity management. Curr Opin Clin Nutr Metab Care 16(6):625–631PubMedGoogle Scholar
  319. Yoneshiro T, Saito M (2015) Activation and recruitment of brown adipose tissue as anti-obesity regimens in humans. Ann Med 47(2):133–141PubMedGoogle Scholar
  320. Yoneshiro T, Aita S, Matsushita M, Okamatsu-Ogura Y, Kameya T, Kawai Y, Miyagawa M, Tsujisaki M, Saito M (2011a) Age-related decrease in cold-activated brown adipose tissue and accumulation of body fat in healthy humans. Obesity 19(9):1755–1760PubMedGoogle Scholar
  321. Yoneshiro T, Aita S, Matsushita M, Kameya T, Nakada K, Kawai Y, Saito M (2011b) Brown adipose tissue, whole-body energy expenditure, and thermogenesis in healthy adult men. Obesity 19(1):13–16PubMedGoogle Scholar
  322. Yoneshiro T, Aita S, Kawai Y, Iwanaga T, Saito M (2012) Nonpungent capsaicin analogs (capsinoids) increase energy expenditure through the activation of brown adipose tissue in humans. Am J Clin Nutr 95(4):845–850PubMedGoogle Scholar
  323. Yoneshiro T, Aita S, Matsushita M, Kayahara T, Kameya T, Kawai Y, Iwanaga T, Saito M (2013) Recruited brown adipose tissue as an antiobesity agent in humans. J Clin Invest 123(8):3404–3408PubMedPubMedCentralGoogle Scholar
  324. Yoneshiro T, Matsushita M, Hibi M, Tone H, Takeshita M, Yasunaga K, Katsuragi Y, Kameya T, Sugie H, Saito M (2017) Tea catechin and caffeine activate brown adipose tissue and increase cold-induced thermogenic capacity in humans, 2. Am J Clin Nutr 105(4):873–881PubMedGoogle Scholar
  325. Yoshida T, Sakane N, Wakabayashi Y, Umekawa T, Kondo M (1994) Anti-obesity and anti-diabetic effects of CL 316, 243, a highly specific β3-adrenoceptor agonist, in yellow KK mice. Life Sci 54(7):491–498PubMedGoogle Scholar
  326. Yoshino S, Kim M, Awa R, Kuwahara H, Kano Y, Kawada T (2014) Kaempferia parviflora extract increases energy consumption through activation of BAT in mice. Food Sci Nutr 2(6):634–637PubMedPubMedCentralGoogle Scholar
  327. Yoshioka M, St-Pierre S, Suzuki M, Tremblay A (1998) Effects of red pepper added to high-fat and high-carbohydrate meals on energy metabolism and substrate utilization in Japanese women. Br J Nutr 80(6):503–510PubMedGoogle Scholar
  328. Yoshitomi H, Yamazaki K, Abe S, Tanaka I (1998) Differential regulation of mouse uncoupling proteins among brown adipose tissue, white adipose tissue, and skeletal muscle in chronic β3Adrenergic receptor agonist treatment. Biochem Biophys Res Commun 253(1):85–91PubMedGoogle Scholar
  329. Young P, Cawthorne M, Levy AL, Wilson K (1984) Reduced maximum capacity of glycolysis in brown adipose tissue of genetically obese, diabetic (db/db) mice and its restoration following treatment with a thermogenic β-adrenoceptor agonist. FEBS Lett 176(1):16–20PubMedGoogle Scholar
  330. Young P, Cawthorne M, Smith S (1985) Brown adipose tissue is a major site of glucose utilisation in C57B16obob mice treated with a thermogenic β-adrenoceptor agonist. Biochem Biophys Res Commun 130(1):241–248PubMedGoogle Scholar
  331. Zhang J, Li Y (2014) Fibroblast growth factor 21, the endocrine FGF pathway and novel treatments for metabolic syndrome. Drug Discov Today 19(5):579–589PubMedGoogle Scholar
  332. Zhang X, Yeung DC, Karpisek M, Stejskal D, Zhou Z-G, Liu F, Wong RL, Chow W-S, Tso AW, Lam KS (2008) Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 57:1246–1253Google Scholar
  333. Zhang Q, Miao Q, Ye H, Zhang Z, Zuo C, Hua F, Guan Y, Li Y (2014) The effects of thyroid hormones on brown adipose tissue in humans: a PET-CT study. Diabetes Metab Res Rev 30(6):513–520PubMedGoogle Scholar
  334. 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):3113–3120PubMedPubMedCentralGoogle Scholar

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©  Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Development, Aging and Regeneration ProgramSanford Burnham Prebys Medical Discovery InstituteLa JollaUSA

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