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  • Review Article
  • Published:

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

Key Points

  • Obesity is a chronic disorder of energy imbalance, whereby a long-term excess of energy intake over expenditure leads to the storage of that excess energy as fat. Pharmacological approaches to the management of obesity include altering the balance between energy intake and expenditure and/or altering the partitioning of nutrients between fat and lean tissue.

  • A reduction in absorbed energy can be achieved by altering the amount and type of food ingested or by interference with its absorption. This could be achieved by amplifying the effects of natural anorexigenic signals. These include the adipocyte-derived hormone leptin, as well as the hypothalamic melanocortins that act downstream of leptin. A wide range of other neuropeptides are now considered to be involved in the control of appetite, and all are potential therapeutic targets.

  • Reducing food intake can also be achieved by interfering with natural orexigenic signals. These include neuropeptide Y, melanin-concentrating hormone, and the recently described stomach-derived hormone ghrelin.

  • Pharmacotherapy targeted at molecular pathways that regulate adaptive thermogenesis provides a plausible means of producing a sustained and safe method of increasing total energy expenditure.

  • Increased expression of novel transcription factors, co-activators and translational regulators, such as PGC1 (peroxisome proliferator-activated receptor-γ co-activator 1), FOXC2 (forkhead box C2) and EIF4EBP1 (eukaryotic-translation-initiation-factor-4E binding protein 1), might promote the development of mitochondrial-rich brown adipocytes in white-adipose-tissue depots.

  • Tissue-specific overexpression of UCP3 (uncoupling protein 3) in skeletal muscle represents a potentially interesting means of preventing diet-induced obesity.

  • Beneficial metabolic effects might be expected from agents that inhibit the accumulation of fat mass relative to lean mass.

  • Inhibitors of peroxisome proliferator-activated receptor-γ (PPARγ) or retinoid X receptor-α (RXRα) function could prevent the differentiation of pre-adipocytes to mature fat cells, therefore limiting adipose-tissue mass.

Abstract

Obesity is associated with numerous health complications, which range from non-fatal debilitating conditions such as osteoarthritis, to life-threatening chronic diseases such as coronary heart disease, diabetes and certain cancers. The psychological consequences of obesity can range from lowered self-esteem to clinical depression. Despite the high prevalence of obesity and the many advances in our understanding of how it develops, current therapies have persistently failed to achieve long-term success. This review focuses on how fat mass can be reduced by altering the balance between energy intake and expenditure.

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Figure 1: Leptin and the regulation of adipose-tissue mass.
Figure 2: Schematic representation of the hypothamalic nuclei.
Figure 3: Proposed mechanism of mammalian adaptive thermogenesis.
Figure 4: Proposed cellular effects of PGC1 expression.
Figure 5: Transcriptional activation through the PPARγ–RXRα heterodimer is crucially important in adipogenesis.

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References

  1. Guerciolini, R. Mode of action of orlistat. Int. J. Obes. Relat. Metab. Disord. 21 (Suppl. 3), S12–S23 (1997).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  3. Montague, C. T. et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903–908 (1997).This paper shows that a single gene defect can cause severe human obesity.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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)].Describes the cloning of leptin and its importance in the regulation of food intake and body weight.

    Article  CAS  PubMed  Google Scholar 

  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).Proof of principle of the importance of leptin in regulating food intake and body weight in humans.

    Article  CAS  PubMed  Google Scholar 

  7. Halaas, J. L. et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269, 543–546 (1995).The first description of the weight-reducing effects of leptin in mice.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  9. Caro, J. F. et al. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 348, 159–161 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Ahima, R. S. et al. Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252 (1996).This paper introduces the role of leptin as a signal of the starved state.

    Article  CAS  PubMed  Google Scholar 

  11. Farooqi, I. S. et al. Metabolism: partial leptin deficiency and human adiposity. Nature 414, 34–35 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Tartaglia, L. A. et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 83, 1263–1271 (1995).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cone, R. D. The central melanocortin system and energy homeostasis. Trends Endocrinol. Metab. 10, 211–216 (1999).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  18. Bertagna, X. Proopiomelanocortin-derived peptides. Endocrinol. Metab. Clin. North Am. 23, 467–485 (1994).

    Article  CAS  PubMed  Google Scholar 

  19. Gantz, I. et al. Molecular cloning of a novel melanocortin receptor. J. Biol. Chem. 268, 8246–8250 (1993).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gantz, I. et al. Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. J. Biol. Chem. 268, 15174–15179 (1993).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  23. Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141 (1997).This paper shows that MC 4 -receptor deficiency causes severe obesity, and crucially that partial deficiency also results in an obese phenotype.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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).With reference 24 , this paper provides evidence that 5% of morbidly obese children might have MC4R mutations, making this the most common monogenic cause of human obesity.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  28. Butler, A. A. et al. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology 141, 3518–3521 (2000).

    Article  CAS  PubMed  Google Scholar 

  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)].

    Article  CAS  PubMed  Google Scholar 

  30. Fan, W. et al. The central melanocortin system can directly regulate serum insulin levels. Endocrinology 141, 3072–3079 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Hartig, P. R. Molecular pharmacology of serotonin receptors. EXS 71, 93–102 (1994).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  33. Nonogaki, K., Strack, A. M., Dallman, M. F. & Tecott, L. H. Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nature Med. 4, 1152–1156 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. Gibbs, J., Young, R. C. & Smith, G. P. Cholecystokinin elicits satiety in rats with open gastric fistulas. Nature 245, 323–325 (1973).

    Article  CAS  PubMed  Google Scholar 

  35. Gibbs, J., Young, R. C. & Smith, G. P. Cholecystokinin decreases food intake in rats. J. Comp. Physiol. Psychol. 84, 488–495 (1973).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Kristensen, P. et al. Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 393, 72–76 (1998).The first description of a role for CART in appetite.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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. Comp. Physiol. 281, R1862–R1867 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Spina, M. et al. Appetite-suppressing effects of urocortin, a CRF-related neuropeptide. Science 273, 1561–1564 (1996).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  45. Van Dijk, G. & Thiele, T. E. Glucagon-like peptide-1 (7–36) amide: a central regulator of satiety and interoceptive stress. Neuropeptides 33, 406–414 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Bray, G. A. Afferent signals regulating food intake. Proc. Nutr. Soc. 59, 373–384 (2000).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  48. Wallenius, V. et al. Interleukin-6-deficient mice develop mature-onset obesity. Nature Med. 8, 75–79 (2002).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Langmead, C. J. et al. Characterization of the binding of [(125)I]-human prolactin releasing peptide (PrRP) to GPR10, a novel G protein coupled receptor. Br. J. Pharmacol. 131, 683–688 (2000).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  52. Howard, A. D. et al. Identification of receptors for neuromedin U and its role in feeding. Nature 406, 70–74 (2000).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  54. Clark, J. T., Kalra, P. S., Crowley, W. R. & Kalra, S. P. Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 115, 427–429 (1984).

    Article  CAS  PubMed  Google Scholar 

  55. Stanley, B. G., Kyrkouli, S. E., Lampert, S. & Leibowitz, S. F. Neuropeptide Y chronically injected into the hypothalamus: a powerful neurochemical inducer of hyperphagia and obesity. Peptides 7, 1189–1192 (1986).

    Article  CAS  PubMed  Google Scholar 

  56. Akabayashi, 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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  60. Blomqvist, A. G. & Herzog, H. Y-receptor subtypes — how many more? Trends Neurosci. 20, 294–298 (1997).

    Article  CAS  PubMed  Google Scholar 

  61. Gerald, C. et al. A receptor subtype involved in neuropeptide-Y-induced food intake. Nature 382, 168–171 (1996).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).Genetic evidence that NPY contributes partly to the hyperphagia seen in leptin deficiency.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Pedrazzini, T. et al. Cardiovascular response, feeding behavior and locomotor activity in mice lacking the NPY Y1 receptor. Nature Med. 4, 722–726 (1998).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  70. Qu, D. et al. A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 380, 243–247 (1996).

    Article  CAS  PubMed  Google Scholar 

  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).The first description of a pathologically lean, hypophagic animal through genetic deletion of an orexigenic factor.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Saito, Y. et al. Molecular characterization of the melanin-concentrating-hormone receptor. Nature 400, 265–269 (1999).

    Article  CAS  PubMed  Google Scholar 

  74. Chambers, J. et al. Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1. Nature 400, 261–265 (1999).Identification of the MCH1 receptor (see also reference 73).

    Article  CAS  PubMed  Google Scholar 

  75. An, S. et al. Identification and characterization of a melanin-concentrating hormone receptor. Proc. Natl Acad. Sci. USA 98, 7576–7581 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kojima, M. et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402, 656–660 (1999).The first identification of a stomach-derived peptide with the capacity to promote feeding.

    Article  CAS  PubMed  Google Scholar 

  78. Nakazato, M. et al. A role for ghrelin in the central regulation of feeding. Nature 409, 194–218 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Tschop, M., Smiley, D. L. & Heiman, M. L. Ghrelin induces adiposity in rodents. Nature 407, 908–913 (2000).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  81. Howard, A. D. et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273, 974–977 (1996).

    Article  CAS  PubMed  Google Scholar 

  82. Gonzalez, S. et al. Identification of endocannabinoids and cannabinoid CB(1) receptor mRNA in the pituitary gland. Neuroendocrinology 70, 137–145 (1999).

    Article  CAS  PubMed  Google Scholar 

  83. Mechoulam, R., Hanus, L. & Fride, E. Towards cannabinoid drugs — revisited. Prog. Med. Chem. 35, 199–243 (1998).

    Article  CAS  PubMed  Google Scholar 

  84. Williams, C. M. & Kirkham, T. C. Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors. Psychopharmacology (Berl.) 143, 315–317 (1999).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  86. Di Marzo, V. et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410, 822–825 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Caulfield, M. P. Muscarinic receptors — characterization, coupling and function. Pharmacol. Ther. 58, 319–379 (1993).

    Article  CAS  PubMed  Google Scholar 

  88. Yamada, M. et al. Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean. Nature 410, 207–212 (2001).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  90. Chemelli, R. M. et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437–451 (1999).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  92. Lowell, B. B. & Spiegelman, B. M. Towards a molecular understanding of adaptive thermogenesis. Nature 404, 652–660 (2000).

    Article  CAS  PubMed  Google Scholar 

  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).

    Google Scholar 

  94. Astrup, A. Thermogenic drugs as a strategy for treatment of obesity. Endocrine 13, 207–212 (2000).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  96. Puigserver, P. et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829–839 (1998).A description of the initial cloning and characterization of PGC1, including its role in the transcriptional co-activation of nuclear hormone receptors and the coordination of adaptive thermogenesis.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  98. Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115–124 (1999).This paper establishes a key role for PGC1 in the regulation of mitochondrial biogenesis and in the regulation of both coupled and uncoupled respiration in muscle.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  101. Scarpulla, R. C. Nuclear control of respiratory chain expression in mammalian cells. J. Bioenerg. Biomembr. 29, 109–119 (1997).

    Article  CAS  PubMed  Google Scholar 

  102. Yoon, J. C. et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413, 131–138 (2001).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  105. Tsukiyama-Kohara, K. et al. Adipose tissue reduction in mice lacking the translational inhibitor 4E-BP1. Nature Med. 7, 1128–1132 (2001).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  107. Fleury, C. et al. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nature Genet. 15, 269–272 (1997).A report of the cloning and characterization of a new UCP homologue with ubiquitous tissue expression, which indicates a role in the pathogenesis of obesity.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).References 108 and 109 outline the cloning and tissue distribution of a second new homologue of UCP with specific muscle and BAT expression.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  113. Golozoubova, V. et al. Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold. FASEB J. 15, 2048–2050 (2001).

    Article  CAS  PubMed  Google Scholar 

  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).This article descibes the Ucp2 knockout mouse and establishes that an obese phenotype is not a feature.

    Article  CAS  PubMed  Google Scholar 

  115. Vidal-Puig, A. J. et al. Energy metabolism in uncoupling protein 3 gene knockout mice. J. Biol. Chem. 275, 16258–16266 (2000).This report describes the phenotype of the Ucp3 knockout mouse, which again is not obese.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  117. Clapham, J. C. et al. Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean. Nature 406, 415–418 (2000).Skeletal-muscle-specific overexpression of Ucp3 in mice leads to an obesity-resistant state despite hyperphagia, with evidence of increased mitochondrial uncoupled respiration.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  119. Klaman, 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).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  120. Smith, S. J. et al. Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat. Nature Genet. 25, 87–90 (2000).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  124. Ruderman, N. & Flier, J. S. Cell biology. Chewing the fat — ACC and energy balance. Science 291, 2558–2559 (2001).

    Article  CAS  PubMed  Google Scholar 

  125. Prins, J. B. & O'Rahilly, S. Regulation of adipose cell number in man. Clin. Sci. (Lond.) 92, 3–11 (1997).

    Article  CAS  Google Scholar 

  126. Danforth, E. Jr. Failure of adipocyte differentiation causes type II diabetes mellitus? Nature Genet. 26, 13 (2000).

    Article  CAS  PubMed  Google Scholar 

  127. Moitra, J. et al. Life without white fat: a transgenic mouse. Genes Dev. 12, 3168–3181 (1998).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  128. Reitman, M. L., Arioglu, E., Gavrilova, O. & Taylor, S. I. Lipoatrophy revisited. Trends Endocrinol. Metab. 11, 410–416 (2000).

    Article  CAS  PubMed  Google Scholar 

  129. Kubota, N. et al. PPAR-γ mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol. Cell. 4, 597–609 (1999).

    Article  CAS  PubMed  Google Scholar 

  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).References 129 and 130 outline the phenotype that is associated with heterozygous Pparg -deficient mice.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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).This paper provides genetic evidence of a role for PPARγ in the regulation of insulin sensitivity, glucose homeostasis and blood pressure in humans.

    Article  CAS  PubMed  Google Scholar 

  133. Anand, A. & Chada, K. In vivo modulation of HMGIC reduces obesity. Nature Genet. 24, 377–380 (2000).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  135. Masuzaki, H. et al. A transgenic model of visceral obesity and the metabolic syndrome. Science 294, 2166–2170 (2001).

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Stephen O'Rahilly.

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DATABASES

LocusLink

β3-adrenoceptor (human)

β3-adrenoceptor (mouse)

AGRP

BDNF

Bdnf

CART

Cart

CB1 cannabinoid receptor

CCK

CCK1 receptor

CHRM3

Chrm3

Cnr1

CNTF

COX II

COX IV

CRF

CRF1 receptor

CRF2 receptor

Dgat

EIF4E

EIF4EBP1

Eif4ebp1

ERα

Foxc2

ghrelin

GHSR

GLP1 receptor

GLUT4

GPR10

HMGIC

Hmgic

HSD11B1

Hsl

5-HT2C receptor

IL-6

Il-6

insulin

leptin

leptin receptor

MC3 receptor

MC4 receptor

Mc3r

Mc4r

MCH

Mch

MCHR1

MCHR2

melanocortin receptors

muscarinic acetylcholine receptors

neuromedin U

neuromedin U receptor 2

NPY

Npy

NPY receptors

Npy1r

Npy2r

NRF1

NRF2

orexin receptors

orexins

perilipin

PGC1

Pgc1

PKA

POMC

PPARα

PPARγ

proglucagon

prolactin-releasing peptide

Ptp1b

RARα

RXRα

TFAM

TRβ

UCP1

Ucp1

UCP2

Ucp2

UCP3

Ucp3

urocortin

Y1 receptor (human)

Y1 receptor (mouse)

Y2 receptor (mouse)

Y5 receptor (human)

Y5 receptor (mouse)

Medscape DrugInfo

orlistat

OMIM

diabetes mellitus

osteoarthritis

sleep apnoea

LINKS

Regeneron Pharmaceuticals

Glossary

WHITE ADIPOSE TISSUE

(WAT). Fat tissue that contains predominantly 'white' adipocytes — cells that specialize in the storage of calorific energy as triglycerides, and its release as free fatty acids in response to changing energy demands.

DYSLIPIDAEMIA

Perturbations in plasma lipid and lipoprotein levels — for example, raised total and/or low-density lipoprotein cholesterol, reduced circulating levels of high-density lipoprotein cholesterol and elevated triglyceride levels — which might be associated with an increased risk of cardiovascular disease.

HYPERPHAGIA

An increased desire to eat.

ARCUATE NUCLEUS

The arc-shaped nucleus at the base of the hypothalamus.

SEROTONERGIC AGONIST

A compound that mimics the actions of serotonin.

OREXIGENIC

Causing an increase in food intake.

ANOREXIGENIC

Causing a reduction in food intake.

CHOLINERGIC

Of the synapses or nerve fibres that liberate acetylcholine.

BROWN ADIPOSE TISSUE

(BAT). Fat tissue that contains predominantly 'brown' adipocytes — cells that have abundant mitochondria (which gives the tissue a brown hue on macroscopic examination) and are specialized in the dissipation of energy through the generation of heat.

PHAEOCHROMOCYTOMA

A catecholamine-secreting tumour that arises from chromaffin cells, usually of the adrenal medulla.

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Crowley, V., Yeo, G. & O'Rahilly, S. Obesity therapy: altering the energy intake-and-expenditure balance sheet. Nat Rev Drug Discov 1, 276–286 (2002). https://doi.org/10.1038/nrd770

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