Cellular bioenergetics as a target for obesity therapy

Nature Reviews Drug Discovery

Volumn 9, Issue 6, 2010, Pages 465-481

  Tseng, Yu Hua ^a   Cypess, Aaron M ^a   Kahn, C Ronald ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 [4 [2 [3 CYCLOHEXYL 1 (4 CYCLOHEXYLBUTYL)UREIDO]ETHYL]PHENYLTHIO] 2 METHYLPROPIONIC ACID; 2,4 DINITROPHENOL; 5 AMINO 4 IMIDAZOLECARBOXAMIDE RIBOSIDE; 6,7 DIHYDRO 4 HYDROXY 3 (2' HYDROXY 1,1' BIPHENYL 4 YL) 6 OXOTHIENO[2,3 B]PYRIDINE 5 CARBONITRILE; ADIPONECTIN; BETAHISTINE; BROMOCRIPTINE; CAFFEINE; CE 326597; CETILISTAT; EPHEDRINE; EXENDIN 4; GROWTH HORMONE; LEPTIN; LIRAGLUTIDE; LORCASERIN; METFORMIN; OSTEOGENIC PROTEIN 1; OXYNTOMODULIN; PHENTERMINE; RESVERATROL; RIVASTIGMINE; SERGLIFLOZIN ETABONATE; SIBUTRAMINE; TESOFENSINE; TETRAHYDROLIPSTATIN; TOPIRAMATE; UNINDEXED DRUG; VENLAFAXINE; ZONISAMIDE;

BARIATRIC SURGERY; BROWN ADIPOSE TISSUE; CALORIC INTAKE; CALORIC RESTRICTION; CELL METABOLISM; CLINICAL TRIAL; DIET THERAPY; DRUG EFFICACY; DRUG SAFETY; DRUG TARGETING; ENERGY EXPENDITURE; EXERCISE; HORMONAL REGULATION; HUMAN; NONHUMAN; OBESITY; PRIORITY JOURNAL; REVIEW; THERMOGENESIS; WEIGHT REDUCTION;

ADENOSINE TRIPHOSPHATE; ADIPOSE TISSUE, BROWN; CELL LINEAGE; ENERGY METABOLISM; HUMANS; ION CHANNELS; MITOCHONDRIA; MITOCHONDRIAL PROTEINS; OBESITY; THERMOGENESIS; TRANSFORMING GROWTH FACTOR BETA;

EID: 77953169046     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd3138     Document Type: Review

References (204)

1. Haslam, D. W. & James, W. P. Obesity. Lancet 366, 1197-1209 (2005).
2. Rolfe, D. F. & Brown, G. C. Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol. Rev. 77, 731-758 (1997).
3. Lowell, B. B. & Spiegelman, B. M. Towards a molecular understanding of adaptive thermogenesis. Nature 404, 652-660 (2000).
4. Wing, R. R. & Phelan, S. Long-term weight loss maintenance. Am. J. Clin. Nutr. 82, 222S-225S (2005).
5. Kaplan, L. M. Pharmacological therapies for obesity. Gastroenterol. Clin. North Am. 34, 91-104 (2005).
6. Welle, S., Forbes, G. B., Statt, M., Barnard, R. R. & Amatruda, J. M. Energy expenditure under free-living conditions in normal-weight and overweight women. Am. J. Clin. Nutr. 55, 14-21 (1992).
7. Melnikova, I. & Wages, D. Anti-obesity therapies. Nature Rev. Drug Discov. 5, 369-370 (2006)
8. Wells, J. C. Thrift: a guide to thrifty genes, thrifty phenotypes and thrifty norms. Int. J. Obes. (Lond.) 33, 1331-11318 (2009).
9. Speakman, J. R. A nonadaptive scenario explaining the genetic predisposition to obesity: the "predation release" hypothesis. Cell. Metab. 6, 5-12 (2007).
10. Padwal, R. S. & Majumdar, S. R. Drug treatments for obesity: orlistat, sibutramine, and rimonabant. Lancet 369, 71-77 (2007).
11. Redman, L. M. et al. Metabolic and behavioral compensations in response to caloric restriction: implications for the maintenance of weight loss. PLoS ONE 4, e4377 (2009).
12. Leibel, R. L., Rosenbaum, M. & Hirsch, J. Changes in energy expenditure resulting from altered body weight. N. Engl. J. Med. 332, 621-628 (1995).
13. Cypess, A. M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509-1517 (2009).
14. Marken Lichtenbelt, W. D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500-1508 (2009).
15. Virtanen, K. A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518-1525 (2009).
16. Saito, M. et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58, 1526-1531 (2009).
17. Zingaretti, M. C. 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. 23, 3113-3120 (2009).
18. Harper, M. E., Green, K. & Brand, M. D. The efficiency of cellular energy transduction and its implications for obesity. Annu. Rev. Nutr. 28, 13-33 (2008).
19. Gosselin, C. & Cote, G. Weight loss maintenance in women two to eleven years after participating in a commercial program: a survey. BMC Womens Health 1, 2 (2001).
20. Tam, J., Fukumura, D. & Jain, R. K. A mathematical model of murine metabolic regulation by leptin: energy balance and defense of a stable body weight. Cell. Metab. 9, 52-63 (2009).
21. Chow, C. C. & Hall, K. D. The dynamics of human body weight change. PLoS Comput. Biol. 4, e1000045 (2008).
22. Green, D. E. & Zande, H. D. Universal energy principle of biological systems and the unity of bioenergetics. Proc. Natl Acad. Sci. USA 78, 5344-5347 (1981).
23. Clapham, J. C. & Arch., J. R. Thermogenic and metabolic antiobesity drugs: rationale and opportunities. Diabetes Obes. Metab. 9, 259-275 (2007).
24. Randle, P. J., Garland, P. B., Hales, C. N. & Newsholme, F. A. The glucose fatty-acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1, 785-789 (1963).
25. Newsholme, E. A. & Crabtree, B. Substrate cycles in metabolic regulation and in heat generation. Biochem. Soc. Symp. 61-109 (1976).
26. Wolfe, R. R., Herndon, D. N., Jahoor, F., Miyoshi, H. & Wolfe, M. Effect of severe burn injury on substrate cycling by glucose and fatty acids. N. Engl. J. Med. 317, 403-408 (1987).
27. Klein, S. & Wolfe, R. R. Whole-body lipolysis and triglyceride-fatty acid cycling in cachectic patients with esophageal cancer. J. Clin. Invest. 86, 1403-1408 (1990).
28. Wolfe, R. R., Klein, S., Carraro, F. & Weber, J. M. Role of triglyceride-fatty acid cycle in controlling fat metabolism in humans during and after exercise. Am. J. Physiol. 258, E382-E389 (1990).
29. Mazzucotelli, A. et al. 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, 2467-2475 (2007).
30. Golozoubova, V. et al. Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold. FASEB J. 15, 2048-2050 (2001).
31. Enerback, S. et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387, 90-94 (1997).
32. Kontani, Y. et al. UCP1 deficiency increases susceptibility to diet-induced obesity with age. Aging Cell 4, 147-155 (2005).
33. Feldmann, H. M., 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. 9, 203-209 (2009).
34. Kopecky, J., Clarke, G., Enerback, S., Spiegelman, B. & Kozak, L. P. Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity. J. Clin. Invest. 96, 2914-2923 (1995).
35. Leonardsson, G. et al. Nuclear receptor corepressor RIP140 regulates fat accumulation. Proc. Natl Acad. Sci. USA 101, 8437-8442 (2004).
36. Foster, D. O. & Frydman, M. L. 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, 257-270 (1979).
37. Mifflin, M. D. et al. A new predictive equation for resting energy expenditure in healthy individuals. Am. J. Clin. Nutr. 51, 241-247 (1990).
38. Rothwell, N. J. & Stock, M. J. Luxuskonsumption, diet-induced thermogenesis and brown fat: the case in favour. Clin. Sci. (Lond.) 64, 19-23 (1983).
39. Bouchard, C. et al. The response to long-term overfeeding in identical twins. N. Engl. J. Med. 322, 1477-1482 (1990).
40. Maes, H. H., Neale, M. C. & Eaves, L. J. Genetic and environmental factors in relative body weight and human adiposity. Behav. Genet. 27, 325-351 (1997).
41. Christiansen, E., Garby, L. & Sorensen, T. I. Quantitative analysis of the energy requirements for development of obesity. J. Theor. Biol. 234, 99-106 (2005).
42. [No authors listed]. Human energy requirements: report of a joint FAO/WHO/UNU expert consultation. Food. Nutr. Bull. 26, 166 (2005).
43. Levine, J. A. Nonexercise activity thermogenesis\liberating the life-force. J. Intern. Med. 262, 273-287 (2007).
44. Stowell, K. M. Malignant hyperthermia: a pharmacogenetic disorder. Pharmacogenomics 9, 1657-1672 (2008).
45. Wijers, S. L., Schrauwen, P., Saris, W. H. & Marken Lichtenbelt, W. D. Human skeletal muscle mito-chondrial uncoupling is associated with cold induced adaptive thermogenesis. PLoS ONE 3, e1777 (2008).
46. Himms-Hagen, J. Exercise in a pill: feasibility of energy expenditure targets. Curr. Drug Targets CNS Neurol. Disord. 3, 389-409 (2004).
47. Lean, M. E., James, W. P., Jennings, G. & Trayhurn, P. Brown adipose tissue uncoupling protein content in human infants, children and adults. Clin. Sci. (Lond.) 71, 291-297 (1986). (Pubitemid 16058739)
48. Neumann, R. O. Experimentelle Beitrage Zur Lehre von den taglichen Nahrungsbedarf des Menschen unter besonderer Bernuksichtigung der notwendigen Eiweissmenge. Archiv fur Hygeine 45, 1-87 (1902) (in German).
49. Rothwell, N. J. & Stock, M. J. A role for brown adipose tissue in diet-induced thermogenesis. Nature 281, 31-35 (1979)
50. Trayhurn, P., Thurlby, P. L. & James, W. P. Thermogenic defect in pre-obese ob/ob mice. Nature 266, 60-62 (1977).
51. Trayhurn, P., Goodbody, A. E. & James, W. P. A role for brown adipose tissue in the genesis of obesity? Studies on experimental animals. Proc. Nutr. Soc. 41, 127-131 (1982).
52. Mercer, S. W. & Trayhurn, P. Effect of high fat diets on energy balance and thermogenesis in brown adipose tissue of lean and genetically obese ob/ob mice. J. Nutr. 11 7, 2147-2153 (1987).
53. Wijers, S. L., Saris, W. H. & Marken Lichtenbelt, W. D. Individual thermogenic responses to mild cold and overfeeding are closely related. J. Clin. Endocrinol. Metab. 92, 4299-4305 (2007).
54. Hosaka, T. et al. Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Proc. Natl Acad. Sci. USA 101, 2975-2980 (2004).
55. Nakamura, K. & Morrison, S. F. Central efferent pathways mediating skin cooling-evoked sympathetic thermogenesis in brown adipose tissue. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R127-R136 (2007).
56. Morrison, S. F., Nakamura, K. & Madden, C. J. Central control of thermogenesis in mammals. Exp. Physiol. 93, 773-797 (2008).
57. Nakamura, K. & Morrison, S. F. A thermosensory pathway that controls body temperature. Nature Neurosci. 11, 62-71 (2008).
58. Zhang, Y. H., Yanase-Fujiwara, M., Hosono, T. & Kanosue, K. Warm and cold signals from the preoptic area: which contribute more to the control of shivering in rats? J. Physiol. 485, 195-202 (1995).
59. Tanaka, M., Owens, N. C, Nagashima, K., Kanosue, K. & McAllen, R. M. Reflex activation of rat fusimotor neurons by body surface cooling, and its dependence on the medullary raphe. J. Physiol. 572, 569-583 (2006).
60. Brown, J. W., Sirlin, E. A., Benoit, A. M., Hoffman, J. M. & Darnall, R. A. Activation of 5-HT1A receptors in medullary raphe disrupts sleep and decreases shivering during cooling in the conscious piglet. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R884-R894 (2008).
61. Vybiral, S., Lesna, I., Jansky, L. & Zeman, V. Thermoregulation in winter swimmers and physiological significance of human catecholamine thermogenesis. Exp. Physiol. 85, 321-326 (2000).
62. van Ooijen, A. M., Marken Lichtenbelt, W. D., van Steenhoven, A. A. & Westerterp, K. R. Cold-induced heat production preceding shivering. Br. J. Nutr. 93, 387-391 (2005).
63. Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277-359 (2004).
64. Golozoubova, V. et al. Depressed thermogenesis but competent brown adipose tissue recruitment in mice devoid of all hormone-binding thyroid hormone receptors. Mol. Endocrinol. 18, 384-401 (2004).
65. Silva, J. E. Thermogenic mechanisms and their hormonal regulation. Physiol. Rev. 86, 435-464 (2006).
66. Mistry, A. M., Swick, A. G. & Romsos, D. R. Leptin rapidly lowers food intake and elevates metabolic rates in lean and ob/ob mice. J. Nutr. 127, 2065-2072 (1997).
67. Commins, S. P. et al. Norepinephrine is required for leptin effects on gene expression in brown and white adipose tissue. Endocrinology 140, 4772-4778 (1999).
68. Elmquist, J. K., Maratos-Flier, E., Saper, C. B. & Flier, J. S. Unraveling the central nervous system pathways underlying responses to leptin. Nature Neurosci. 1, 445-449 (1998).
69. Harris, R. B. Leptin\much more than a satiety signal. Annu. Rev. Nutr. 20, 45-75 (2000).
70. Rosenbaum, M. et al. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J. Clin. Invest. 115, 3579-3586 (2005).
71. Ferrannini, E. et al. Insulin: new roles for an ancient hormone. Eur. J. Clin. Invest. 29, 842-852 (1999).
72. Weyer, C, Bogardus, C, Mott, D. M. & Pratley, R. E. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J. Clin. Invest. 104, 787-794 (1999).
73. 3-adrenoceptor agonist. Biochem. Pharmacol. 54, 121-131 (1997). (Pubitemid 27353229)
74. Guerra, C, Koza, R. A., Yamashita, H., Walsh, K. & Kozak, L. P. Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity. J. Clin. Invest. 102, 412-420 (1998)
75. Lowell, B. B. et al. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 366, 740-742 (1993).
76. Heaton, J. M. The distribution of brown adipose tissue in the human. J. Anat. 112, 35-39 (1972).
77. Astrup, A. Thermogenesis in human brown adipose tissue and skeletal muscle induced by sympathomimetic stimulation. Acta Endocrinol. Suppl. (Copenh.) 278, 1-32 (1986).
78. Weyer, C, Tataranni, P. A., Snitker, S., Danforth, E. Jr & Ravussin, E. Increase in insulin action and fat oxidation after treatment with CL 316,243, a highly selective ^-adrenoceptor agonist in humans. Diabetes 47, 1555-1561 (1998).
79. 3-adrenergic receptor agonist, on energy expenditure and body composition in obese men. Am. J. Clin. Nutr. 76, 780-788 (2002).
80. Cunningham, S. et al. The characterization and energetic potential of brown adipose tissue in man. Clin. Sci. (Lond.) 69, 343-348 (1985).
81. Nedergaard, J., Bengtsson, T. & Cannon, B. Unexpected evidence for active brown adipose tissue in adult humans. Am. J. Physiol. Endocrinol. Metab. 293, E444-E452 (2007).
82. Schoder, H., Larson, S. M. & Yeung, H. W. PET/CT in oncology: integration into clinical management of lymphoma, melanoma, and gastrointestinal malignancies. J. Nucl. Med. 45 (Suppl. 1), 72-81 (2004).
83. Hany, T. F. et al. 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, 1393-1398 (2002).
84. 18F-FDG PET/CT. J. Nucl. Med. 44, 170-176 (2003).
85. Ravussin, E. & Kozak, L. P. Have we entered the brown adipose tissue renaissance? Obes. Rev. 10, 265-268 (2009).
86. Almind, K., Manieri, M., Sivitz, W. I., Cinti, S. & Kahn, C. R. Ectopic brown adipose tissue in muscle provides a mechanism for differences in risk of metabolic syndrome in mice. Proc. Natl Acad. Sci. USA 104, 2366-2371 (2007).
87. Xue, B. et al. Genetic variability affects the development of brown adipocytes in white fat but not in interscapular brown fat. J. Lipid Res. 48, 41-51 (2007).
88. 18F-FDG PET/CT. J. Nucl. Med. 44, 1267-1270 (2003).
89. Gesta, S., Tseng, Y. H. & Kahn, C. R. Developmental origin of fat: tracking obesity to its source. Cell 1 31, 242-256 (2007).
90. Atit, R. et al. β-Catenin activation is necessary and sufficient to specify the dorsal dermal fate in the mouse. Dev. Biol. 296, 164-176 (2006).
91. Timmons, J. A. et al. Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages. Proc. Natl Acad. Sci. USA 104, 4401-4406 (2007).
92. Seale, P. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961-967 (2008).
93. Petrovic, N. et al. 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 classical brown adipocytes. J. Biol. Chem. 285, 7153-7164 (2010).
94. Cinti, S. Transdifferentiation properties of adipocytes in the adipose organ. Am. J. Physiol. Endocrinol. Metab. 297, E977-E986 (2009).
95. Fink, B. D. et al. Mitochondrial proton leak in obesity-resistant and obesity-prone mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R1773-R1780 (2007).
96. Lean, M. E. J. & James, W. P. T. in Brown Adipose Tissue (eds Trayhurn, P. & Nicholls, D. G.) 339-365 (Edward Arnold, London, 1986).
97. Choy, L. & Derynck, R. Transforming growth factor-β inhibits adipocyte differentiation by Smad3 interacting with CCAAT/enhancer-binding protein (C/EBP) and repressing C/EBP transactivation function. J. Biol. Chem. 278, 9609-9619 (2003).
98. Alessi, M. C. et al. Plasminogen activator inhibitor 1, transforming growth factor-β1, and BMI are closely associated in human adipose tissue during morbid obesity. Diabetes 49, 1374-1380 (2000).
99. Samad, F., Yamamoto, K., Pandey, M. & Loskutoff, D. J. Elevated expression of transforming growth factor-β in adipose tissue from obese mice. Mol. Med. 3, 37-48 (1997).
100. Schulz, T. J. & Tseng, Y. H. Emerging role of bone morphogenetic proteins in adipogenesis and energy metabolism. Cytokine. Growth Factor Rev. 20, 523-531 (2009).
101. Tseng, Y. H. et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454, 1000-1004 (2008).
102. Shen, J. J. et al. Deficiency of growth differentiation factor 3 protects against diet-induced obesity by selectively acting on white adipose. Mol. Endocrinol. 23, 113-123 (2009).
103. Yamashita, H. et al. Basic fibroblast growth factor (bFGF) contributes to the enlargement of brown adipose tissue during cold acclimation. Pflugers Arch. 428, 352-356 (1994).
104. Konishi, M., Mikami, T., Yamasaki, M., Miyake, A. & Itoh, N. Fibroblast growth factor-16 is a growth factor for embryonic brown adipocytes. J. Biol. Chem. 275, 12119-12122 (2000).
105. Tomlinson, E. et al. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology 143, 1741-1747 (2002).
106. Badman, M. K. et al. Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states. Cell. Metab. 5, 426-437 (2007).
107. Kharitonenkov, A. et al. FGF-21 as a novel metabolic regulator. J. Clin. Invest. 11 5, 1627-1635 (2005).
108. Mori, K. et al. Disruption of klotho gene causes an abnormal energy homeostasis in mice. Biochem. Biophys. Res. Commun. 278, 665-670 (2000).
109. Tseng, Y. H., Kriauciunas, K. M., Kokkotou, E. & Kahn, C. R. Differential roles of insulin receptor substrates in brown adipocyte differentiation. Mol. Cell Biol. 24, 1918-1929 (2004).
110. Fasshauer, M. et al. Essential role of insulin receptor substrate-2 in insulin stimulation of glut4 translocation and glucose uptake in brown adipocytes. J. Biol. Chem. 275, 25494-25501 (2000).
111. Tseng, Y. H., Ueki, K., Kriauciunas, K. M. & Kahn, C. R. Differential roles of insulin receptor substrates in the anti-apoptotic function of insulin-like growth factor-1 and insulin. J. Biol. Chem. 277, 31601-31611 (2002).
112. Levine, J. A., Eberhardt, N. L. & Jensen, M. D. Role of nonexercise activity thermogenesis in resistance to fat gain in humans. Science 283, 212-214 (1999).
113. Badjatia, N. et al. Predictors and clinical implications of shivering during therapeutic normothermia. Neurocrit. Care 6, 186-191 (2007).
114. Goodyear, L. J. The exercise pill\too good to be true? N. Engl. J. Med. 359, 1842-1844 (2008).
115. Puigserver, P. et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829-839 (1998).
116. Lin, J. et al. Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres. Nature 418, 797-801 (2002).
117. 2+ ATPase isoform 1 heat production. Endocrinology 149, 6262-6271 (2008).
118. Nelson, D. L. & Gehlert, D. R. Central nervous system biogenic amine targets for control of appetite and energy expenditure. Endocrine 29, 49-60 (2006).
119. Astrup, A., Bulow, J., Madsen, J. & Christensen, N. J. Contribution of BAT and skeletal muscle to thermogenesis induced by ephedrine in man. Am. J. Physiol. 248, E507-E515 (1985).
120. Elabd, C. et al. Human multipotent adipose-derived stem cells differentiate into functional brown adipocytes. Stem Cells 27, 2753-2760 (2009).
121. Crisan, M. et al. A reservoir of brown adipocyte progenitors in human skeletal muscle. Stem Cells 26, 2425-2433 (2008).
122. Tobin, J. F. & Celeste, A. J. Bone morphogenetic proteins and growth differentiation factors as drug targets in cardiovascular and metabolic disease. Drug Discov. Today 11, 405-411 (2006).
123. Li, T., Surendran, K., Zawaideh, M. A., Mathew, S. & Hruska, K. A. Bone morphogenetic protein 7: a novel treatment for chronic renal and bone disease. Curr. Opin. Nephrol. Hypertens. 13, 417-422 (2004).
124. Wang, S. et al. Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy. Kidney Int. 63, 2037-2049 (2003).
125. Chou, J. et al. Neuroregenerative effects of BMP7 after stroke in rats. J. Neurol. Sci. 240, 21-29 (2006).
126. Harvey, B. K. et al. Neurotrophic effects of bone morphogenetic protein-7 in a rat model of Parkinson's disease. Brain Res. 1022, 88-95 (2004).
127. Zuch, C. L. et al. Beneficial effects of intraventricularly administered BMP-7 following a striatal 6-hydroxydopamine lesion. Brain Res. 1010, 10-16 (2004).
128. Zeisberg, E. M. et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nature Med. 13, 952-961 (2007).
129. Sugimoto, H. et al. BMP-7 functions as a novel hormone to facilitate liver regeneration. FASEB J. 21, 256-264 (2007).
130. Beenken, A. & Mohammadi, M. The FGF family: biology, pathophysiology and therapy. Nature Rev. Drug Discov. 8, 235-253 (2009).
131. Seale, P. et al. Transcriptional control of brown fat determination by PRDM16. Cell. Metab. 6, 38-54 (2007).
132. Hansen, J. B. et al. Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation. Proc. Natl Acad. Sci. USA 101, 4112-4117 (2004).
133. Tseng, Y. H. et al. Prediction of preadipocyte differentiation by gene expression reveals role of insulin receptor substrates and necdin. Nature Cell Biol. 7, 601-611 (2005).
134. Shekelle, P. G. et al. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis. JAMA 289, 1537-1545 (2003).
135. 18F-FDG in brown adipose tissue. J. Nucl. Med. 48, 981-986 (2007).
136. Magkos, F & Kavouras, S. A. Caffeine use in sports, pharmacokinetics in man, and cellular mechanisms of action. Crit. Rev. Food. Sci. Nutr. 45, 535-562 (2005).
137. Huang, Z. L. et al. Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nature Neurosci. 8, 858-859 (2005).
138. Dhar, R. et al. Cardiovascular toxicities of performance-enhancing substances in sports. Mayo Clin. Proc. 80, 1307-1315 (2005).
139. Boozer, C. N. et al. Herbal ephedra/caffeine for weight loss: a 6-month randomized safety and efficacy trial. Int. J. Obes. Relat Metab. Disord. 26, 593-604 (2002).
140. De Matteis, R. et al. Immunohistochemical identification of the adrenoceptor in intact human adipocytes and ventricular myocardium: effect of obesity and treatment with ephedrine and caffeine. Int. J. Obes. Relat Metab. Disord. 26, 1442-1450 (2002).
141. Arch., J. R. The discovery of drugs for obesity, the metabolic effects of leptin and variable receptor pharmacology: perspectives from-adrenoceptor agonists. Naunyn Schmiedebergs. Arch. Pharmacol. 378, 225-240 (2008)
142. 3-adrenergic receptor agonist, on energy expenditure in obese men. Clin. Pharmacol. Ther. 71, 272-279 (2002).
143. Colman, E. Dinitrophenol and obesity: an early twentieth-century regulatory dilemma. Regul. Toxicol. Pharmacol. 48, 115-117 (2007).
144. Baxter, J. D. & Webb, P. Thyroid hormone mimetics: potential applications in atherosclerosis, obesity and type 2 diabetes. Nature Rev. Drug Discov. 8, 308-320 (2009).
145. Villicev, C. M. et al. Thyroid hormone receptor beta-specific agonist GC-1 increases energy expenditure and prevents fat-mass accumulation in rats. J. Endocrinology 193, 21-29 (2007).
146. Bryzgalova, G. et al. Anti-obesity, anti-diabetic, and lipid lowering effects of the thyroid receptor (3 subtype selective agonist KB-141. J. Steroid Biochem. Mol. Biol. 111, 262-267 (2008).
147. Watanabe, M. et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439, 484-489 (2006).
148. Thomas, C. et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell. Metab. 10, 167-177 (2009).
149. Tiwari, A. & Maiti, P. TGR5: an emerging bile acid G-protein-coupled receptor target for the potential treatment of metabolic disorders. Drug Discov. Today 14, 523-530 (2009).
150. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425-432 (1994).
151. Friedman, J. M. Leptin at 14 y of age: an ongoing story. Am. J. Clin. Nutr. 89, 973S-979S (2009).
152. Bluher, S. & Mantzoros, C. S. Leptin in humans: lessons from translational research. Am. J. Clin. Nutr 89, 991S-997S (2009).
153. Welt, C. K. et al. Recombinant human leptin in women with hypothalamic amenorrhea. N. Engl. J. Med. 351, 987-997 (2004).
154. Roth, J. D. et al. Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc. Natl Acad. Sci. USA 105, 7257-7262 (2008).
155. Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1a. Cell 127, 1109-1122 (2006).
156. Baur, J. A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337-342 (2006).
157. Yamamoto, H., Schoonjans, K. & Auwerx, J. Sirtuin functions in health and disease. Mol. Endocrinol. 21, 1745-1755 (2007).
158. Feige, J. N. et al. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell. Metab. 8, 347-358 (2008).
159. Koh, H. J., Brandauer, J. & Goodyear, L. J. LKB1 and AMPK and the regulation of skeletal muscle metabolism. Curr. Opin. Clin. Nutr. Metab. Care 11, 227-232 (2008).
160. + metabolism and SIRT 1 activity. Nature 458, 1056-1060 (2009).
161. Narkar, V. A. et al. AMPK and PPARS agonists are exercise mimetics. Cell 134, 405-415 (2008).
162. Ruderman, N. B., Saha, A. K. & Kraegen, E. W Minireview: malonyl CoA, AMP-activated protein kinase, and adiposity. Endocrinology 144, 5166-5171 (2003).
163. Guigas, B. et al. Beyond AICA riboside: in search of new specific AMP-activated protein kinase activators. IUBMB Life 61, 18-26 (2009).
164. Lou, P. H. et al. Mitochondrial uncouplers with an extraordinary dynamic range. Biochem. J. 407, 129-140 (2007).
165. Rosen, E. D. & MacDougald, O. A. Adipocyte differentiation from the inside out. Nature Rev. Mol. Cell Biol. 7, 885-896 (2006).
166. Hansen, J. B. & Kristiansen, K. Regulatory circuits controlling white versus brown adipocyte differentiation. Biochem. J. 398, 153-168 (2006).
167. Farmer, S. R. Molecular determinants of brown adipocyte formation and function. Genes. Dev 22, 1269-1275 (2008).
168. Scime, A. et al. Rb and p 107 regulate preadipocyte differentiation into white versus brown fat through repression of PGC-1a. Cell. Metab. 2, 283-295 (2005).
169. Kiskinis, E. et al. RIP 140 directs histone and DNA methylation to silence Ucp1 expression in white adipocytes. EMBO J. 26, 4831-4840 (2007).
170. Powelka, A. M. et al. Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP 140 in mouse adipocytes. J. Clin. Invest. 116, 125-136 (2006).
171. Kajimura, S. et al. Regulation of the brown and white fat gene programs through a PRDM 16/CtBP transcriptional complex. Genes. Dev. 22, 1397-1409 (2008).
172. Kajimura, S. et al. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-p transcriptional complex. Nature 460, 1154-1158 (2009).
173. Chiu, Y. H., Lee, T. H. & Shen, W W Use of low-dose topiramate in substance use disorder and bodyweight control. Psychiatry Clin. Neurosci. 61, 630-633 (2007).
174. Gadde, K. M., Franciscy, D. M., Wagner, H. R. & Krishnan, K. R. Zonisamide for weight loss in obese adults: a randomized controlled trial. JAMA 289, 1820-1825 (2003).
175. Musi, N. & Goodyear, L. J. Insulin resistance and improvements in signal transduction. Endocrine 29, 73-80 (2006).
176. English, P. J. et al. Metformin prolongs the postprandial fall in plasma ghrelin concentrations in type 2 diabetes. Diabetes Metab. Res. Rev. 23, 299-303 (2007).
177. Ahima, R. S. et al. Appetite suppression and weight reduction by a centrally active aminosterol. Diabetes 51, 2099-2104 (2002).
178. Sowers, J. R. Endocrine functions of adipose tissue: focus on adiponectin. Clin. Cornerstone 9, 32-38 (2008)
179. Bays, H. E. Current and investigational antiobesity agents and obesity therapeutic treatment targets. Obes. Res. 12, 1197-1211 (2004).
180. Ravussin, E. et al. Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity (Silver Spring) 17, 1736-1743 (2009).
181. Remesar, X. et al. Oral oleoyl-estrone induces the rapid loss of body fat in Zucker lean rats fed a hyperlipidic diet. Int. J. Obes. Relat. Metab. Disord. 24, 1405-1412 (2000).
182. McCarthy, A. A. When enough is too much: new strategies to treat obesity. Chem. Biol. 11, 1025-1026 (2004).
183. Chaudhri, O. B., Wynne, K. & Bloom, S. R. Can gut hormones control appetite and prevent obesity? Diabetes Care 31 (Suppl. 2), 284-289 (2008).
184. Glazer, G. Long-term pharmacotherapy of obesity 2000: a review of efficacy and safety. Arch. Intern. Med. 161, 1814-1824 (2001).
185. Hansen, R. A., Gartlehner, G., Lohr, K. N. & Kaufer, D. I. Functional outcomes of drug treatment in Alzheimer's disease: a systematic review and meta-analysis. Drugs Aging 24, 155-167 (2007).
186. Astrup, A. et al. Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial. Lancet 372, 1906-1913 (2008).
187. Appolinario, J. C., Bueno, J. R. & Coutinho, W. Psychotropic drugs in the treatment of obesity: what promise? CNS Drugs 18, 629-651 (2004).
188. Dwoskin, L. P., Rauhut, A. S., King-Pospisil, K. A. & Bardo, M. T. Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent. CNS Drug Rev. 12, 178-207 (2006).
189. Chandra, R. & Liddle, R. A. Cholecystokinin. Curr. Opin. Endocrinol. Diabetes Obes. 14, 63-67 (2007).
190. 2C agonist, reduces body weight in obese men and women. Obesity (Silver Spring) 17, 494-503 (2009).
191. Van der Ploeg, L. H. et al. Design and synthesis of (ant)-agonists that alter appetite and adiposity. Prog. Brain Res. 153, 107-118 (2006).
192. Adan, R. A. et al. The MC4 receptor and control of appetite. Br. J. Pharmacol. 149, 815-827 (2006).
193. Barak, N., Greenway, F. L., Fujioka, K., Aronne, L. J. & Kushner, R. F. Effect of histaminergic manipulation on weight in obese adults: a randomized placebo controlled trial. Int. J. Obes. (Lond.) 32, 1559-1565 (2008).
194. Greenway, F. L. et al. Rational design of a combination medication for the treatment of obesity. Obesity (Silver Spring) 17, 30-39 (2009).
195. Li, J. et al. In vitro and in vivo profile of 5-[(4′-trifluoro methyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid benzylmethyl carbamoylamide (dirlotapide), a novel potent MTP inhibitor for obesity. Bioorg. Med. Chem. Lett. 17, 1996-1999 (2007).
196. Idris, I. & Donnelly, R. Sodium-glucose co-transporter-2 inhibitors: an emerging new class of oral antidiabetic drug. Diabetes Obes. Metab. 11, 79-88 (2009).
197. Carlson, M. J. & Cummings, D. E. Prospects for an anti-ghrelin vaccine to treat obesity. Mol. Interv. 6, 249-252 (2006).
198. Morton, N. M. & Seckl, J. R. 11β-hydroxysteroid dehydrogenase type 1 and obesity. Front. Horm. Res. 36, 146-164 (2008).
199. Hartman, M. L. et al. Growth hormone replacement therapy in adults with growth hormone deficiency improves maximal oxygen consumption independently of dosing regimen or physical activity. J. Clin. Endocrinol. Metab. 93, 125-130 (2008).
200. Ruderman, N. B. et al. AMPK as a metabolic switch in rat muscle, liver and adipose tissue after exercise. Acta Physiol. Scand. 178, 435-442 (2003).
201. Ahmadian, M. et al. Adipose overexpression of desnutrin promotes fatty acid use and attenuates diet-induced obesity. Diabetes 58, 855-866 (2009).
202. Kok, P. et al. Activation of dopamine D2 receptors simultaneously ameliorates various metabolic features of obese women. Am. J. Physiol. Endocrinol. Metab. 291, E1038-E1043 (2006).
203. Wang, Y. X. et al. Peroxisome-proliferator-activated receptor δ activates fat metabolism to prevent obesity. Cell 11 3, 159-170 (2003).
204. Buckley, J. D. & Howe, P. R. Anti-obesity effects of long-chain omega-3 polyunsaturated fatty acids. Obes. Rev. 10, 648-659 (2009).