Obesity therapy: Altering the energy intake-and-expenditure balance sheet

Nature Reviews Drug Discovery

Volumn 1, Issue 4, 2002, Pages 276-286

  Crowley, Vivion E F ^a   Yeo, Giles S H ^b   O'Rahilly, Stephen ^a  

^a Addenbrooke's Hospital   (United Kingdom)

^b UNIVERSITY OF CAMBRIDGE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

(3 CHLOROPHENYL)PIPERAZINE; ANOREXIGENIC AGENT; ANTILIPEMIC AGENT; BRAIN DERIVED NEUROTROPHIC FACTOR; CANNABINOID RECEPTOR ANTAGONIST; CHOLECYSTOKININ RECEPTOR BLOCKING AGENT; DEXFENFLURAMINE; G PROTEIN COUPLED RECEPTOR; GHRELIN; GLUCAGON LIKE PEPTIDE 1; INTERLEUKIN 6; LEPTIN RECEPTOR; MELANIN CONCENTRATING HORMONE; MELANOCORTIN RECEPTOR; NEUROPEPTIDE RECEPTOR; NEUROPEPTIDE Y; NEUROPEPTIDE Y RECEPTOR; NEUROPEPTIDE Y RECEPTOR ANTAGONIST; NORFENFLURAMINE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PROOPIOMELANOCORTIN; RECOMBINANT CILIARY NEUROTROPHIC FACTOR; RECOMBINANT LEPTIN; RETINOIC ACID RECEPTOR ALPHA; RETINOID X RECEPTOR; RIMONABANT; SEROTONIN 2C AGONIST; SEROTONIN 2C RECEPTOR; TRIACYLGLYCEROL LIPASE; UNINDEXED DRUG; CARRIER PROTEIN; CELL SURFACE RECEPTOR; CORTICOTROPIN RECEPTOR; HORMONE RECEPTOR; HYPOPHYSIS HORMONE; HYPOTHALAMUS HORMONE; LEPTIN; MELANIN; MELANIN CONCENTRATING HORMONE RECEPTOR; MELANIN-CONCENTRATING HORMONE; MELANIN-CONCENTRATING HORMONE RECEPTOR; MUSCARINIC M1 RECEPTOR; MUSCARINIC RECEPTOR;

ADIPOSE TISSUE; BINDING AFFINITY; CALORIC INTAKE; CLINICAL TRIAL; DEPRESSION; DIABETES MELLITUS; DISEASE ASSOCIATION; DRUG RECEPTOR BINDING; DRUG TARGETING; ENERGY EXPENDITURE; HUMAN; ISCHEMIC HEART DISEASE; METABOLIC BALANCE; MOUSE; NONHUMAN; NUTRIENT UPTAKE; OBESITY; OSTEOARTHRITIS; PRIORITY JOURNAL; RECEPTOR BLOCKING; REVIEW; RISK ASSESSMENT; SELF ESTEEM; SIGNAL TRANSDUCTION; THERMOGENESIS; BROWN ADIPOSE TISSUE; ENERGY METABOLISM; GENETIC TRANSCRIPTION; METABOLISM; PHYSIOLOGY;

ADIPOSE TISSUE, BROWN; CARRIER PROTEINS; ENERGY INTAKE; ENERGY METABOLISM; HUMANS; HYPOTHALAMIC HORMONES; LEPTIN; MELANINS; NEUROPEPTIDE Y; OBESITY; PITUITARY HORMONES; PRO-OPIOMELANOCORTIN; RECEPTOR, MUSCARINIC M1; RECEPTORS, CELL SURFACE; RECEPTORS, CORTICOTROPIN; RECEPTORS, MELANOCORTIN; RECEPTORS, MUSCARINIC; RECEPTORS, PITUITARY HORMONE; TRANSCRIPTION, GENETIC;

EID: 0036528005     PISSN: 14741776     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrd770     Document Type: Review

References (135)

1. Guerciolini, R. Mode of action of orlistat. Int. J. Obes. Relat. Metab. Disord. 21 (Suppl. 3), S12-S23 (1997).
2. Hill, J. O. et al. Orlistat, a lipase inhibitor, for weight maintenance after conventional dieting: a 1-year study. Am. J. Clin. Nutr. 69, 1108-1116 (1999).
3. Montague, C. T. et al. Congenital eptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903-908 (1997).
4. Strobel, A., Issad, T., Camoin, L., Ozata, M. & Strosberg, A. D. A leptin missense mutation associated with hypogonadism and morbid obesity. Nature Genet. 18, 213-215 (1998).
5. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425-432 (1994) [erratum in 374, 479 (1995)].
6. Farooqi, I. S. et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N. Engl. J. Med. 341, 879-884 (1999).
7. Halaas, J. L. et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269, 543-546 (1995).
8. Heymsfield, S. B. et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 282, 1568-1575 (1999).
9. Caro, J. F. et al. Decreased cerebrospinal-fluid/serum eptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 348, 159-161 (1996).
10. Ahima, R. S. et al. Role of leptin in the neuroendocrine response to fasting. Nature 382, 250-252 (1996).
11. Farooqi, I. S. et al. Metabolism: partial leptin deficiency and human adiposity. Nature 414, 34-35 (2001).
12. Tartaglia, L. A. et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 83, 1263-1271 (1995).
13. Sleeman, M. W., Anderson, K. D., Lambert, P. D., Yancopoulos, G. D. & Wiegand, S. J. The ciliary neurotrophic factor and its receptor, CNTFRα. Pharm. Acta Helv. 74, 265-272 (2000).
14. Lambert, P. D. et al. Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity. Proc. Natl Acad. Sci. USA 98, 4652-4657 (2001).
15. Cone, R. D. The central melanocortin system and energy homeostasis. Trends Endocrinol. Metab. 10, 211-216 (1999).
16. Yeo, G. S., Farooqi, I. S., Challis, B. G., Jackson, R. S. & O'Rahilly, S. The role of melanocortin signalling in the control of body weight: evidence from human and murine genetic models. Q. J. Med. 93, 7-14 (2000).
17. Thornton, J. E., Cheung, C. C., Clifton, D. K. & Steiner, R. A. Regulation of hypothalamic proopiomelanocortin mRNA by leptin in ob/ob mice. Endocrinology 138, 5063-5066 (1997).
18. Bertagna, X. Proopiomelanocortin-derived peptides. Endocrinol. Metab. Clin. North Am. 23, 467-485 (1994).
19. Gantz, I. et al. Molecular cloning of a novel melanocortin receptor. J. Biol. Chem. 268, 8246-8250 (1993).
20. Roselli-Rehfuss, L. et al. Identification of a receptor for γ-melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. Proc. Natl Acad. Sci. USA 90, 8856-8860 (1993).
21. Gantz, I. et al. Molecular cloning, expression, and gene localization of a fourth melanocorlin receptor. J. Biol. Chem. 268, 15174-15179 (1993).
22. Mountjoy, K. G., Mortrud, M. T., Low, M. J., Simerly, R. B. & Cone, R. D. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol. Endocrinol. 8, 1298-1308 (1994).
23. Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131-141 (1997).
24. Farooqi, I. S. et al. Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J. Clin. Invest. 106, 271-279 (2000).
25. Vaisse, C. et al. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J. Clin. Invest. 106, 253-262 (2000).
26. Hinney, A. et al. Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans. J. Clin. Endocrinol. Metab. 84, 1483-1486 (1999).
27. Chen, A. S. et al. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nature Genet. 26, 97-102 (2000).
28. Butler, A. A. et al. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology 141, 3518-3521 (2000).
29. Ollmann, M. M. et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135-138 (1997) [erratum in 281, 1615 (1997)].
30. Fan, W. et al. The central melanocortin system can directly regulate serum insulin levels. Endocrinology 141, 3072-3079 (2000).
31. Hartig, P. R. Molecular pharmacology of serotonin receptors. EXS 71, 93-102 (1994).
32. Curzon, G., Gibson, E. L. & Oluyomi, A. O. Appetite suppression by commonly used drugs depends on 5-HT receptors but not on 5-HT availability. Trends Pharmacol. Sci. 18, 21-25 (1997).
33. 2C receptor gene. Nature Med. 4, 1152-1156 (1998).
34. Gibbs, J., Young, R. C. & Smith, G. P. Cholecystokinin elicits satiety in rats with open gastric fistulas. Nature 245, 323-325 (1973).
35. Gibbs, J., Young, R. C. & Smith, G. P. Cholecystokinin decreases food intake in rats. J. Comb. Physiol. Psychol. 84, 488-495 (1973).
36. Niederau, C., Liddle, R. A., Williams, J. A. & Grendell, J. H. Pancreatic growth: interaction of exogenous cholecystokinin, a protease inhibitor, and a cholecystokinin receptor antagonist in mice. Gut 28 (Suppl.), 63-69 (1987).
37. Kristensen, P. et al. Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 393, 72-76 (1998).
38. Asnicar, M. A. et al. Absence of cocaine- and amphetamine-regulated transcript results in obesity in mice fed a high caloric diet. Endocrinology 142, 4394-4400 (2001).
39. Aja, S., Sahandy, S., Ladenheim, E. E., Schwartz, G. J. & Moran, T. H. Intracerebroventricular CART peptide reduces food intake and alters motor behavior at a hindbrain site. Am. J. Physiol. Regul. Integr. Comb. Physiol. 281, R1862-R1867 (2001).
40. Spina, M. et al. Appetite-suppressing effects of urocortin, a CRF-related neuropeptide. Science 273, 1561-1564 (1996).
41. Arase, K., York, D. A., Shimizu, H., Shargill, N. & Bray, G. A. Effects of corticotropin-releasing factor on food intake and brown adipose tissue thermogenesis in rats. Am. J. Physiol. 255, E255-E259 (1988).
42. Coste, S. C. et al. Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor 2. Nature Genet. 24, 403-409 (2000).
43. Bale, T. L. et al. Mice deficient for corticotropin-releasing hormone receptor 2 display anxiety-like behaviour and are hypersensitive to stress. Nature Genet. 24, 410-414 (2000).
44. Bradbury, M. J., McBurnie, M. I., Denton, D. A., Lee, K. F. & Vale, W. W. Modulation of urocortin-induced hypophagia and weight loss by corticotropin-releasing factor receptor 1 deficiency in mice. Endocrinology 141, 2715-2724 (2000).
45. Van Dijk, G. & Thiele, T. E. Glucagon-like peptide-1 (7-36) amide: a central regulate of satiety and interoceptive stress. Neuropeptides 33, 406-414 (1999).
46. Bray, G. A. Afferent signals regulating food intake. Proc. Nutr. Soc. 59, 373-384 (2000).
47. Scrocchi, L. A. et al. Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nature Med. 2, 1254-1258 (1996).
48. Wallenius, V. et al. Interleukin-6-deficient mice develop mature-onset obesity. Nature Med. 8, 75-79 (2002).
49. Kernie, S. G., Liebl, D. J. & Parada, L. F. BDNF regulates eating behavior and locomotor activity in mice. EMBO J. 19, 1290-1300 (2000).
50. Langmead, C. J. et al. Characterization of the binding of [(125)I]-human prolactin releasing peptide (PrRP) to GRP10, a novel G protein coupled receptor. Br. J. Pharmacol. 131, 683-688 (2000).
51. Lawrence, C. B., Celsi, F., Brennand, J. & Luckman, S. M. Alternative role for prolactin-releasing peptide in the regulation of food intake. Nature Neurosci. 3, 645-646 (2000).
52. Howard, A. D. et al. Identification of receptors for neuromedin U and its role in feeding. Nature 406, 70-74 (2000).
53. Stanley, B. G. & Leibowitz, S. F. Neuropeptide Y: stimulation of feeding and drinking by injection into the paraventricular nucleus. Life Sci. 35, 2635-2642 (1984).
54. Clark, J. T., Kalra, P. S., Crowley, W. R. & kara, S. P. Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 115, 427-429 (1984).
55. Stanley, B. G., Kyrkouli, S. E., Lambert, S. & Leibowitz, S. F. Neuropeptide Y chronically injected into the hypothalamus: a powerful neurochemical inducer of hyperphagia and obesity. Peptides 7, 1189-1192 (1986).
56. Akabayasi, A., Wahlestedt, C., Alexander, J. T. & Leibowitz, S. F. Specific inhibition of endogenous neuropeptide Y synthesis in arcuate nucleus by antisense oligonucleotides suppresses feeding behavior and insulin secretion. Brain Res. Mol. Brain Res. 21, 55-61 (1994).
57. Shibasaki, T., Oda, T., Imaki, T., Ling, N. & Demura, H. Injection of anti-neuropeptide Y γ-globulin into the hypothalamic paraventricular nucleus decreases food intake in rats. Brain Res. 601, 313-316 (1993).
58. Chen, P., Li, C., Haskell-Luevano, C., Cone, R. D. & Smith, M. S. Altered expression of agouti-related protein and its colocalization with neuropeptide Y in the arcuate nucleus of the hypothalamus during lactation. Endocrinology 140, 2645-2650 (1999).
59. Stephens, T. W. et al. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 377, 530-532 (1995).
60. Blomqvist, A. G. & Herzog, H. Y-receptor subtypes - how many more? Trends Neurosci. 20, 294-298 (1997).
61. Gerald, C. et al. A receptor subtype involved in neuropeptide-Y-induced food intake. Nature 382, 168-171 (1996).
62. Erickson, J. C., Clegg, K. E. & Palmiter, R. D. Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature 381, 415-421 (1996).
63. Erickson, J. C., Hollopeter, G. & Palmiter, R. D. Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science 274, 1704-1707 (1996).
64. Kushi, A. et al. Obesity and mild hyperinsulinemia found in neuropeptide Y Y1 receptor-deficient mice. Proc. Natl Acad. Sci. USA 95, 15659-15664 (1998).
65. Pedrazzini, T. et al. Cardiovascular response, feeding behavoir and locomotor activity in mice lacking the NPY Y1 receptor. Nature Med. 4, 722-726 (1998).
66. Naveilhan, P. et al. Normal feeding behavior, body weight and leptin response require the neuropeptide Y Y2 receptor. Nature Med. 5, 1188-1193 (1999).
67. Marsh, D. J., Hollopeter, G., Kafer, K. E. & Palmiter, R. D. Role of the Y5 neuropeptide Y receptor in feeding and obesity. Nature Med. 4, 718-721 (1998).
68. Bittencourt, J. C. et al. The melanin-concentrating hormone system of the rat brain: an immuno- and hybridization histochemical characterization. J. Comp. Neurol. 319, 218-245 (1992).
69. Skofitsch, G., Jacobowitz, D. M. & Zamir, N. Immunohistochemical localization of a melanin concentrating hormone-like peptide in the rat brain. Brain Res. Bull. 15, 635-649 (1985).
70. Qu, D. et al. A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 380, 243-247 (1996).
71. Shimada, M., Tritos, N. A., Lowell, B. B., Flier, J. S. & Maratos-Flier, E. Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature 396, 670-674 (1998).
72. Ludwig, D. S. et al. Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance. J. Clin. Invest. 107, 379-386 (2001).
73. Saito, Y. et al. Molecular characterization of the melanin-concentrating-hormone receptor. Nature 400, 265-269 (1999).
74. Chambers, J. et al. Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-couped receptor SLC-1. Nature 400, 261-265 (1999).
75. An, S. et al. Identification and characterization of a melanin-concentrating hormone receptor. Proc. Natl Acad. Sci. USA 98, 7576-7581 (2001).
76. Sailer, A. W. et al. Identification and characterization of a second melanin-concentrating hormone receptor, MCH-2R. Proc. Natl Acad. Sci. USA 98, 7564-7569 (2001).
77. Kojima, M. et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402, 656-660 (1999).
78. Nakazato, M. et al. A role for ghrelin in the central regulation of feeding. Nature 409, 194-218 (2001).
79. Tschop, M., Smiley, D. L. & Heiman, M. L. Ghrelin induces adiposity in rodents. Nature 407, 908-913 (2000).
80. Guan, X. M. et al. Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res. Mol. Brain Res. 48, 23-29 (1997).
81. Howard, A. D. et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273, 974-977 (1996).
82. Gonzalez, S. et al. Identification of endocannabinoids and cannabinoid CB(1) receptor mRNA in the pituitary gland. Neuroendocrinology 70, 137-145 (1999).
83. Mechoulam, R., Hanus, L. & Ends, E. Towards cannabinoid drugs - revisited. Prog. Med. Chem. 35, 199-243 (1998).
84. Williams, C. M. & Kirkham, T. C. Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors. Psychopharmacology (Berl.) 143, 315-317 (1999).
85. Hao, S., Avraham, Y., Mechoulam, R. & Berry, E. M. Low dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice. Eur. J. Pharmacol. 392, 147-156 (2000).
86. Di Marzo, V. et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410, 822-825 (2001).
87. Caulfield, M. P. Muscarinic receptors - characterization, coupling and function. Pharmacol. Ther. 58, 319-379 (1993).
88. 3 muscarinic acetylcholine receptor are hypophagic and lean. Nature 410, 207-212 (2001).
89. Sakurai, T. et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior Cell 92, 573-585 (1998).
90. Chemelli, R. M. et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437-451 (1999).
91. Lin, L. et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98, 365-376 (1999).
92. Lowell, B. B. & Spiegelman, B. M. Towards a molecular understanding of adaptive thermogenesis. Nature 404, 652-660 (2000).
93. Himms-Hagen, J. & Ricquier, D. in Handbook of Obesity (eds Bray, G. A., Bouchard, C. & James, W. P. T.) 415-441 (Marcel Dekker, New York, 1998).
94. Astrup, A. Thermogenic drugs as a strategy for treatment of obesity. Endocrine 13, 207-212 (2000).
95. Weyer, C., Gautier, J. F.,& Danforth, E. Jr. Development of β3-adrenoceptor agonists for the treatment of obesity and diabetes - an update. Diabetes Metab. 25, 11-21 (1999).
96. Puigserver, P. et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829-839 (1998).
97. Vega, R. B., Huss, J. M. & Kelly, D. P. The coactivator PGC-1 cooperates with peroxisome proliferator activated receptor-α in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol. Cell. Biol. 20, 1868-1876 (2000).
98. Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115-124 (1999).
99. Virbasius, J. V. & Scarpulla, R. C. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc. Natl Acad. Sci. USA 91, 1309-1313 (1994).
100. Gugneja, S., Virbasius, C. M. & Scarpulla, R. C. Nuclear respiratory factors 1 and 2 utilize similar glutamine-containing clusters of hydrophobic residues to activate transcription. Mol. Cell. Biol. 16, 5708-5716 (1996).
101. Scarpulla, R. C. Nuclear control of respiratory chain expression in mammalian cells. J. Bioenerg. Biomembr. 29, 109-119 (1997).
102. Yoon, J. C. et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413, 131-138 (2001).
103. Michael, L. F. et al. Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1. Proc. Natl Acad. Sci. USA 98, 3820-3825 (2001).
104. Cederberg, A. et al. FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. Cell 106, 563-573 (2001).
105. Tsukiyama-Kohara, K. et al. Adipose tissue reduction in mice lacking the translational inhibitor 4E-BP1. Nature Med. 7, 1128-1132 (2001).
106. Rolfe, D. F. & Brand, M. D. The physiological significance of mitochondrial proton leak in animal cells and tissues. Biosci. Rep. 17, 9-16 (1997).
107. Fleury, C. et al. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nature Genet. 15, 269-272 (1997).
108. Boss, O. et al. Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression. FEBS Lett. 408, 39-42 (1997).
109. Vidal-Puig, A., Solanes, G., Grujic, D., Flier, J. S. & Lowell, B. B. UCP3: an uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue. Biochem. Biophys. Res. Commun. 235, 79-82 (1997).
110. Solanes, G., Vidal-Puig, A., Grujic, D., Flier, J. S. & Lowell, B. B. The human uncoupling protein-3 gene. Genomic structure, chromosomal localization, and genetic basis for short and long form transcripts. J. Biol. Chem. 272, 25433-25436 (1997).
111. Bouchard, C., Perusse, L., Chagnon, Y. C., Warden, C. & Ricquier, D. Linkage between markers in the vicinity of the uncoupling protein 2 gene and resting metabolic rate in humans. Hum. Mol. Genet. 6, 1887-1889 (1997).
112. Walder, K. et al. Association between uncoupling protein polymorphisms (UCP2-UCP3) and energy metabolism/obesity in Pima indians. Hum. Mol. Genet. 7, 1431-1435 (1998).
113. Golozoubova, V. et al. Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold. FASEB J. 15, 2048-2050 (2001).
114. Zhang, C. Y. et al. Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, β-cell dysfunction, and type 2 diabetes. Cell 105, 745-755 (2001).
115. Vidal-Puig, A. J. et al. Energy metabolism in uncoupling protein 3 gene knockout mice. J. Biol. Chem. 275, 16258-16266 (2000).
116. Cline, G. W. et al. In vivo effects of uncoupling protein-3 gene disruption on mitochondrial energy metabolism. J. Biol. Chem. 276, 20240-20244 (2001).
117. Clapham, J. C. et al. Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean. Nature 406, 415-418 (2000).
118. Elchebly, M. et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283, 1544-1548 (1999).
119. Kleman, L. D. et al. Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol. Cell. Biol. 20, 5479-5489 (2000).
120. Smith, S. J. et al. Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat. Nature Genet. 25, 87-90 (2000).
121. Martinez-Botas, J. et al. Absence of perilipin results in leanness and reverses obesity in Lepr (db/db) mice. Nature Genet. 26, 474-479 (2000).
122. Tansey, J. T. et al. Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity. Proc. Natl Acad. Sci. USA 98, 6494-6499 (2001).
123. Abu-Elheiga, L., Matzuk, M. M., Abo-Hashema, K. A. & Wakil, S. J. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 291, 2613-2616 (2001).
124. Ruderman, N. & Flier, J. S. Cell biology. Chewing the fat - ACC and energy balance. Science 291, 2558-2559 (2001).
125. Prins, J. B. & O'Rahilly, S. Regulation of adipose cell number in man. Clin. Sci. (Lond.) 92, 3-11 (1997).
126. Danforth, E. Jr. Failure of adipocyte differentiation causes type II diabetes mellitus? Nature Genet. 26, 13 (2000).
127. Moitra, J. et al. Life without white tat: a transgenic mouse. Genes Dev. 12, 3168-3181 (1998).
128. Reitman, M. L., Arioglu, E., Gavrilova, O. & Taylor, S. I. Lipoatrophy revisited. Trends Endocrinol Metab. 11, 410-416 (2000).
129. Kubota, N. et al. PPAR-γ mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol. Cell. 4, 597-609 (1999).
130. Miles, P. D., Barak, Y., He, W., Evans, R. M. & Olefsky, J. M. Improved insulin-sensitivity in mice heterozygous for PPAR-γ deficiency. J. Clin. Invest. 105, 287-292 (2000).
131. Yamauchi, T. et al. Inhibition of RXR and PPARγ ameliorates diet-induced obesity and type 2 diabetes. J. Clin. Invest. 108, 1001-1013 (2001).
132. Barroso, I. et al. Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 402, 880-883 (1999).
133. Anand, A. & Chada, K. In vivo modulation of HMGIC reduces obesity. Nature Genet. 24, 377-380 (2000).
134. Munzer, T. et al. Effects of GH and/or sex steroid administration on abdominal subcutaneous and visceral fat in healthy aged women and men. J. Clin. Endocrinol. Metab. 86, 3604-3610 (2001).
135. Masuzaki, H. et al. A transgenic model of visceral obesity and the metabolic syndrome. Science 294, 2166-2170 (2001).