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  • Review Article
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Limitations in anti-obesity drug development: the critical role of hunger-promoting neurons

Key Points

  • Hunger is the adaptive response to the need for higher energy levels, and promotes cellular and behavioural shifts that lead to changes in cognition and other higher brain functions.

  • Hunger is characteristic of a negative energy balance — for example, owing to calorie restriction — and promotion of these pathways leads to extended healthy lifespan. By contrast, promotion of satiety (a positive energy balance) leads to metabolic overload and chronic disorders.

  • Hunger and satiety are primarily controlled by the hypothalamus through two populations of neurons: the neuropeptide Y/agouti-related protein (NPY/AgRP) neurons and the pro-opiomelanocortin (POMC) neurons. NPY/AgRP neurons are active during negative energy balance, whereas POMC neurons are active during positive energy balance.

  • During a state of negative energy balance, the activity of NPY/AgRP neurons is sustained mainly by burning free fatty acids, and maintaining low levels of reactive oxygen species (ROS). POMC neurons, on the other hand, utilize mainly carbohydrates (glucose) as fuel, and their sustained activation during a state of long-term positive energy balance is correlated with high levels of ROS and tissue damage.

  • Most of the anti-obesity therapies are designed to promote satiety, with the exception of orlistat (a lipase inhibitor), which, together with lorcaserin and Qsymia (a combination of phentermine plus topiramate) are the only drugs approved by the US Food and Drug Administration for the long-term treatment of obesity. However, promotion of satiety leads to chronic disorders and consequently severe side effects.

  • New drug therapies for the chronic treatment of obesity should therefore focus on promoting the pathways involved in negative energy balance, such as those that are activated during calorie restriction and exercise.

  • Several new drugs being developed to treat obesity aim to target peripheral tissues, mainly the white adipose tissue, instead of the brain to avoid severe side effects. However, as peripheral tissues and the brain are interconnected, it is unlikely that one compound will be specific to one tissue during chronic treatment programmes.

  • We therefore propose that current obesity therapies should only be used for short periods of time, in conjunction with intense behavioural interventions. Moreover, targeting the molecular pathways that mediate the beneficial effects of such behavioural interventions (for example, calorie restriction and exercise) may represent a safer alternative therapeutic approach for the treatment of chronic metabolic disorders such as obesity.

Abstract

Current anti-obesity drugs aim to reduce food intake by either curbing appetite or suppressing the craving for food. However, many of these agents have been associated with severe psychiatric and/or cardiovascular side effects, highlighting the need for alternative therapeutic strategies. Emerging knowledge on the role of the hypothalamus in enabling the central nervous system to adapt to the changing environment — by managing peripheral tissue output and by regulating higher brain functions — may facilitate the discovery of new agents that are more effective and have an acceptable benefit–risk profile. Targeting the molecular pathways that mediate the beneficial effects of calorie restriction and exercise may represent an alternative therapeutic approach for the treatment of chronic metabolic disorders such as obesity.

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Figure 1: Humoral and nutritional crosstalk between peripheral tissues and the brain.
Figure 2: Summary of known mechanisms in the arcuate nucleus and MC4 receptor target areas involved in obesity in humans.
Figure 3: Mechanism of action of the main anti-obesity drugs currently in the market or recently withdrawn.
Figure 4: Relationship between the metabolic state and ROS production.
Figure 5: Alternative strategies for the development of improved anti-obesity pharmacotherapies.

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References

  1. Finucane, M. M. et al. National, regional, and global trends in body–mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet 377, 557–567 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Ioannides-Demos, L. L., Piccenna, L. & McNeil, J. J. Pharmacotherapies for obesity: past, current, and future therapies. J. Obes. 2011, 179674 (2011).

    Article  PubMed  CAS  Google Scholar 

  3. Jones, D. Suspense builds on anti-obesity rollercoaster ride. Nature Rev. Drug Discov. 10, 5–6 (2011).

    Article  CAS  Google Scholar 

  4. Huntington, M. K. & Shewmake, R. A. Anti-obesity drugs: are they worth it? Future Med. Chem. 3, 267–269 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. Powell, A. G., Apovian, C. M. & Aronne, L. J. New drug targets for the treatment of obesity. Clin. Pharmacol. Ther. 90, 40–51 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Ben-Dor, M., Gopher, A., Hershkovitz, I. & Barkai, R. Man the fat hunter: the demise of Homo erectus and the emergence of a new hominin lineage in the Middle Pleistocene (ca. 400 kyr) Levant. PLoS ONE 6, e28689 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Eaton, S. B. & Konner, M. Paleolithic nutrition. A consideration of its nature and current implications. N. Engl. J. Med. 312, 283–289 (1985).

    Article  CAS  PubMed  Google Scholar 

  8. Leonard, W. R. Food for thought. Dietary change was a driving force in human evolution. Sci. Am. 287, 106–115 (2002).

    Article  PubMed  Google Scholar 

  9. Thompson, R. F. The neurobiology of learning and memory. Science 233, 941–947 (1986).

    Article  CAS  PubMed  Google Scholar 

  10. Seeley, R. J. & Woods, S. C. Monitoring of stored and available fuel by the CNS: implications for obesity. Nature Rev. Neurosci. 4, 901–909 (2003).

    Article  CAS  Google Scholar 

  11. Cone, R. Studies on the physiological functions of the melanocortin system. Endocr. Rev. 27, 736–749 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Gao, Q. & Horvath, T. L. Neurobiology of feeding and energy expenditure. Annu. Rev. Neurosci. 30, 367–398 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Fontana, L. Modulating human aging and age-associated diseases. Biochim. Biophys. Acta 1790, 1133–1138 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Piper, M. D. W. & Bartke, A. Diet and aging. Cell Metab. 8, 99–104 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Fontana, L., Partridge, L. & Longo, V. D. Extending healthy life span — from yeast to humans. Science 328, 321–326 (2010). A comprehensive review on the effects of calorie restriction on lifespan.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hetherington, A. W. & Ranson, S. W. Hypothalamic lesions and adiposity in the rat. Anat. Rec. 78, 149–172 (1940).

    Article  Google Scholar 

  17. Hetherington, A. W. & Ranson, S. W. The relation of various hypothalamic lesions to adiposity in the rat. J. Comp. Neurol. 76, 475–499 (1942).

    Article  Google Scholar 

  18. Hetherington, A. W. Non-production of hypothalamic obesity in the rat by lesions rostral or dorsal to the ventro-medial hypothalamic nuclei. J. Comp. Neurol. 80, 33–45 (1944).

    Article  Google Scholar 

  19. Anand, B. K. & Brobeck, J. R. Hypothalamic control of food intake in rats and cats. Yale J. Biol. Med. 24, 123–140 (1951).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Anand, B. K. & Brobeck, J. R. Localization of a “feeding center” in the hypothalamus of the rat. Proc. Soc. Exp. Biol. Med. 77, 323–324 (1951).

    Article  CAS  PubMed  Google Scholar 

  21. De Lecea, L. et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl Acad. Sci. USA 95, 322–327 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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 

  23. Qu, D. Q. 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 

  24. Olney, J. W. Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science 164, 719–721 (1969).

    Article  CAS  PubMed  Google Scholar 

  25. Luquet, S., Perez, F., Hnasko, T. & Palmiter, R. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 310, 683–685 (2005). Reports the crucial role of the NPY/AgRP neurons in adult mice; ablation of these neurons leads to death.

    Article  CAS  PubMed  Google Scholar 

  26. Wu, Q., Boyle, M. & Palmiter, R. Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell 137, 1225–1234 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Gropp, E. et al. Agouti-related peptide-expressing neurons are mandatory for feeding. Nature Neurosci. 8, 1289–1291 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Bewick, G. et al. Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype. FASEB J. 19, 1680–1682 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Dietrich, M. O. & Horvath, T. L. GABA keeps up an appetite for life. Cell 137, 1177–1179 (2009).

    Article  PubMed  Google Scholar 

  30. Hahn, T., Breininger, J., Baskin, D. & Schwartz, M. Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nature Neurosci. 1, 271–272 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Horvath, T., Naftolin, F., Kalra, S. & Leranth, C. Neuropeptide-Y innervation of β-endorphin-containing cells in the rat mediobasal hypothalamus: a light and electron microscopic double immunostaining analysis. Endocrinology 131, 2461–2467 (1992). The first demonstration of the connectivity between the NPY/AgRP neurons and the neighbouring POMC cells.

    Article  CAS  PubMed  Google Scholar 

  32. Horvath, T. L., Bechmann, I., Naftolin, F., Kalra, S. P. & Leranth, C. Heterogeneity in the neuropeptide Y-containing neurons of the rat arcuate nucleus: GABAergic and non-GABAergic subpopulations. Brain Res. 756, 283–286 (1997). The first demonstration that NPY/AgRP neurons also produce GABA.

    Article  CAS  PubMed  Google Scholar 

  33. 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 

  34. Cowley, M. et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480–484 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Pinto, S. et al. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304, 110–115 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Ollmann, M. M. et al. Antagonism of central melanocortin receptors in vitro and in vivo by Agouti-related protein. Science 278, 135–138 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Qian, S. et al. Neither agouti-related protein nor neuropeptide Y is critically required for the regulation of energy homeostasis in mice. Mol. Cell. Biol. 22, 5027–5035 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wu, Q., Howell, M. P. & Palmiter, R. D. Ablation of neurons expressing agouti-related protein activates Fos and gliosis in postsynaptic target regions. J. Neurosci. 28, 9218–9226 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994). Reports the discovery of leptin.

    Article  CAS  PubMed  Google Scholar 

  40. Halaas, J. L. et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269, 543–546 (1995). Reports the effects of leptin in maintaining weight in mammals.

    Article  CAS  PubMed  Google Scholar 

  41. Farooqi, I. S. Genetic aspects of severe childhood obesity. Pediatr. Endocrinol. Rev. 3 (Suppl. 4), 528–536 (2006).

    PubMed  Google Scholar 

  42. Farooqi, I. S. Monogenic human obesity syndromes. Prog. Brain Res. 153, 119–125 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Farooqi, I. S. et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N. Engl. J. Med. 356, 237–247 (2007). A comprehensive description of a series of mutations in the leptin receptor that lead to obesity in humans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hummel, K. P., Dickie, M. M. & Coleman, D. L. Diabetes, a new mutation in the mouse. Science 153, 1127–1128 (1966).

    Article  CAS  PubMed  Google Scholar 

  45. 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 

  46. Chen, H. et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84, 491–495 (1996).

    Article  CAS  PubMed  Google Scholar 

  47. Montague, C. T. et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903–908 (1997).

    Article  CAS  PubMed  Google Scholar 

  48. 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).

    Article  CAS  PubMed  Google Scholar 

  49. Considine, R. V. et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N. Engl. J. Med. 334, 292–295 (1996).

    Article  CAS  PubMed  Google Scholar 

  50. Maffei, M. et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nature Med. 1, 1155–1161 (1995).

    Article  CAS  PubMed  Google Scholar 

  51. Halaas, J. L. et al. Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc. Natl Acad. Sci. USA 94, 8878–8883 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Cusin, I., Rohner-Jeanrenaud, F., Stricker-Krongrad, A. & Jeanrenaud, B. The weight-reducing effect of an intracerebroventricular bolus injection of leptin in genetically obese fa/fa rats. Reduced sensitivity compared with lean animals. Diabetes 45, 1446–1450 (1996).

    Article  CAS  PubMed  Google Scholar 

  53. Vaisse, C. et al. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nature Genet. 14, 95–97 (1996).

    Article  CAS  PubMed  Google Scholar 

  54. Cone, R. D. Anatomy and regulation of the central melanocortin system. Nature Neurosci. 8, 571–578 (2005). A comprehensive review about the melanocortin system.

    Article  CAS  PubMed  Google Scholar 

  55. Ozcan, L. et al. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 9, 35–51 (2009).

    Article  CAS  PubMed  Google Scholar 

  56. Ozcan, U. et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457–461 (2004).

    Article  PubMed  CAS  Google Scholar 

  57. Ozcan, U. et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313, 1137–1140 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Diano, S. et al. Peroxisome proliferation-associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity. Nature Med. 17, 1121–1127 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Toro, A. A. et al. Pex3p-dependent peroxisomal biogenesis initiates in the endoplasmic reticulum of human fibroblasts. J. Cell Biochem. 107, 1083–1096 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Titorenko, V. I. & Mullen, R. T. Peroxisome biogenesis: the peroxisomal endomembrane system and the role of the ER. J. Cell Biol. 174, 11–17 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Schluter, A. et al. The evolutionary origin of peroxisomes: an ER-peroxisome connection. Mol. Biol. Evol. 23, 838–845 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Andrews, Z. B. et al. UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals. Nature 454, 846–851 (2008). Describes the mechanisms that govern the activity of NPY/AgRP neurons in response to ghrelin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Horvath, T. L., Andrews, Z. B. & Diano, S. Fuel utilization by hypothalamic neurons: roles for ROS. Trends Endocrinol. Metab. 20, 78–87 (2009). A comprehensive review describing the role of ROS in the hypothalamus.

    Article  CAS  PubMed  Google Scholar 

  64. Horvath, T. L. et al. Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proc. Natl Acad. Sci. USA 107, 14875–14880 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Thaler, J. P. et al. Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 122, 153–162 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. Cruickshank, C. C. & Dyer, K. R. A review of the clinical pharmacology of methamphetamine. Addiction 104, 1085–1099 (2009).

    Article  PubMed  Google Scholar 

  67. Frohmader, K. S., Pitchers, K. K., Balfour, M. E. & Coolen, L. M. Mixing pleasures: review of the effects of drugs on sex behavior in humans and animal models. Horm. Behav. 58, 149–162 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. Garfield, A. S. & Heisler, L. K. Pharmacological targeting of the serotonergic system for the treatment of obesity. J. Physiol. 587, 49–60 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. Saller, C. F. & Stricker, E. M. Hyperphagia and increased growth in rats after intraventricular injection of 5,7-dihydroxytryptamine. Science 192, 385–387 (1976).

    Article  CAS  PubMed  Google Scholar 

  70. Fletcher, P. J. & Paterson, I. A. A comparison of the effects of tryptamine and 5-hydroxytryptamine on feeding following injection into the paraventricular nucleus of the hypothalamus. Pharmacol. Biochem. Behav. 32, 907–911 (1989).

    Article  CAS  PubMed  Google Scholar 

  71. Heisler, L. K. et al. Activation of central melanocortin pathways by fenfluramine. Science 297, 609–611 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Choi, S., Blake, V., Cole, S. & Fernstrom, J. D. Effects of chronic fenfluramine administration on hypothalamic neuropeptide mRNA expression. Brain Res. 1087, 83–86 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Heisler, L. K. et al. Serotonin reciprocally regulates melanocortin neurons to modulate food intake. Neuron 51, 239–249 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Lam, D. D. et al. Serotonin 5-HT2C receptor agonist promotes hypophagia via downstream activation of melanocortin 4 receptors. Endocrinology 149, 1323–1328 (2008).

    Article  CAS  PubMed  Google Scholar 

  75. Guerciolini, R. Mode of action of orlistat. Int. J. Obes. Relat. Metab. Disord. 21 (Suppl. 3), 12–23 (1997).

    Google Scholar 

  76. Hartmann, D., Hussain, Y., Guzelhan, C. & Odink, J. Effect on dietary fat absorption of orlistat, administered at different times relative to meal intake. Br. J. Clin. Pharmacol. 36, 266–270 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Drent, M. L. et al. Orlistat (Ro 18-0647), a lipase inhibitor, in the treatment of human obesity: a multiple dose study. Int. J. Obes. Relat. Metab. Disord. 19, 221–226 (1995).

    CAS  PubMed  Google Scholar 

  78. James, W. P., Avenell, A., Broom, J. & Whitehead, J. A one-year trial to assess the value of orlistat in the management of obesity. Int. J. Obes. Relat. Metab. Disord. 21 (Suppl. 3), 24–30 (1997).

    Google Scholar 

  79. Padwal, R. Cetilistat, a new lipase inhibitor for the treatment of obesity. Curr. Opin. Investig. Drugs 9, 414–421 (2008).

    CAS  PubMed  Google Scholar 

  80. Yamada, Y., Kato, T., Ogino, H., Ashina, S. & Kato, K. Cetilistat (ATL-962), a novel pancreatic lipase inhibitor, ameliorates body weight gain and improves lipid profiles in rats. Horm. Metab. Res. 40, 539–543 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. Kopelman, P. et al. Cetilistat (ATL-962), a novel lipase inhibitor: a 12-week randomized, placebo-controlled study of weight reduction in obese patients. Int. J. Obes. (Lond.) 31, 494–499 (2007).

    Article  CAS  Google Scholar 

  82. Bryson, A., de la Motte, S. & Dunk, C. Reduction of dietary fat absorption by the novel gastrointestinal lipase inhibitor cetilistat in healthy volunteers. Br. J. Clin. Pharmacol. 67, 309–315 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kopelman, P. et al. Weight loss, HbA1c reduction, and tolerability of cetilistat in a randomized, placebo-controlled phase 2 trial in obese diabetics: comparison with orlistat (Xenical). Obesity (Silver Spring) 18, 108–115 (2010).

    Article  CAS  Google Scholar 

  84. Hollander, P. A. et al. Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year randomized double-blind study. Diabetes Care 21, 1288–1294 (1998).

    Article  CAS  PubMed  Google Scholar 

  85. Heymsfield, S. B. et al. Effects of weight loss with orlistat on glucose tolerance and progression to type 2 diabetes in obese adults. Arch. Intern. Med. 160, 1321–1326 (2000).

    Article  CAS  PubMed  Google Scholar 

  86. Kelley, D. E. et al. Clinical efficacy of orlistat therapy in overweight and obese patients with insulin-treated type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care 25, 1033–1041 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Miles, J. M. et al. Effect of orlistat in overweight and obese patients with type 2 diabetes treated with metformin. Diabetes Care 25, 1123–1128 (2002).

    Article  CAS  PubMed  Google Scholar 

  88. Hanefeld, M. & Sachse, G. The effects of orlistat on body weight and glycaemic control in overweight patients with type 2 diabetes: a randomized, placebo-controlled trial. Diabetes Obes. Metab. 4, 415–423 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Guy-Grand, B. et al. International trial of long-term dexfenfluramine in obesity. Lancet 2, 1142–1145 (1989).

    Article  CAS  PubMed  Google Scholar 

  90. Mathus-Vliegen, E. M., van de Voorde, K., Kok, A. M. & Res, A. M. Dexfenfluramine in the treatment of severe obesity: a placebo-controlled investigation of the effects on weight loss, cardiovascular risk factors, food intake and eating behaviour. J. Intern. Med. 232, 119–127 (1992).

    Article  CAS  PubMed  Google Scholar 

  91. Jick, H. et al. A population-based study of appetite-suppressant drugs and the risk of cardiac-valve regurgitation. N. Engl. J. Med. 339, 719–724 (1998).

    Article  CAS  PubMed  Google Scholar 

  92. Loke, Y. K., Derry, S. & Pritchard-Copley, A. Appetite suppressants and valvular heart disease — a systematic review. BMC Clin. Pharmacol. 2, 6 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Abenhaim, L. et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N. Engl. J. Med. 335, 609–616 (1996).

    Article  CAS  PubMed  Google Scholar 

  94. Devereux, R. B. Appetite suppressants and valvular heart disease. N. Engl. J. Med. 339, 765–766 (1998).

    Article  CAS  PubMed  Google Scholar 

  95. Centers for Disease Control and Prevention. Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: US Department of Health and Human Services interim public health recommendations, November 1997. JAMA 278, 1729–1731 (1997).

  96. Delcroix, M., Kurz, X., Walckiers, D., Demedts, M. & Naeije, R. High incidence of primary pulmonary hypertension associated with appetite suppressants in Belgium. Eur. Respir. J. 12, 271–276 (1998).

    Article  CAS  PubMed  Google Scholar 

  97. Weintraub, M., Rubio, A., Golik, A., Byrne, L. & Scheinbaum, M. L. Sibutramine in weight control: a dose-ranging, efficacy study. Clin. Pharmacol. Ther. 50, 330–337 (1991).

    Article  CAS  PubMed  Google Scholar 

  98. Bray, G. A. et al. A double-blind randomized placebo-controlled trial of sibutramine. Obes. Res. 4, 263–270 (1996).

    Article  CAS  PubMed  Google Scholar 

  99. Rolls, B. J., Shide, D. J., Thorwart, M. L. & Ulbrecht, J. S. Sibutramine reduces food intake in non-dieting women with obesity. Obes. Res. 6, 1–11 (1998).

    Article  CAS  PubMed  Google Scholar 

  100. Seagle, H. M., Bessesen, D. H. & Hill, J. O. Effects of sibutramine on resting metabolic rate and weight loss in overweight women. Obes. Res. 6, 115–121 (1998).

    Article  CAS  PubMed  Google Scholar 

  101. Hanotin, C., Thomas, F., Jones, S. P., Leutenegger, E. & Drouin, P. A comparison of sibutramine and dexfenfluramine in the treatment of obesity. Obes. Res. 6, 285–291 (1998).

    Article  CAS  PubMed  Google Scholar 

  102. Bray, G. A. et al. Sibutramine produces dose-related weight loss. Obes. Res. 7, 189–198 (1999).

    Article  CAS  PubMed  Google Scholar 

  103. Tambascia, M. A. et al. Sibutramine enhances insulin sensitivity ameliorating metabolic parameters in a double-blind, randomized, placebo-controlled trial. Diabetes Obes. Metab. 5, 338–344 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Sanchez-Reyes, L. et al. Use of sibutramine in overweight adult hispanic patients with type 2 diabetes mellitus: a 12-month, randomized, double-blind, placebo-controlled clinical trial. Clin. Ther. 26, 1427–1435 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Garcia-Morales, L. M. et al. Use of sibutramine in obese mexican adolescents: a 6-month, randomized, double-blind, placebo-controlled, parallel-group trial. Clin. Ther. 28, 770–782 (2006).

    Article  CAS  PubMed  Google Scholar 

  106. Lindholm, A. et al. Effect of sibutramine on weight reduction in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Fertil. Steril. 89, 1221–1228 (2008).

    Article  CAS  PubMed  Google Scholar 

  107. Cota, D. et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J. Clin. Invest. 112, 423–431 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Addy, C. et al. The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake. Cell Metab. 7, 68–78 (2008).

    Article  CAS  PubMed  Google Scholar 

  109. Rinaldi-Carmona, M. et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 350, 141240–141244 (1994).

    Article  Google Scholar 

  110. Rinaldi-Carmona, M. et al. Biochemical and pharmacological characterisation of SR141716A, the first potent and selective brain cannabinoid receptor antagonist. Life Sci. 56, 141941–141947 (1995).

    Article  Google Scholar 

  111. Després, J.-P. et al. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N. Engl. J. Med. 353, 2121–2134 (2005).

    Article  PubMed  Google Scholar 

  112. Van Gaal, L. F. et al. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 365, 1389–1397 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Pi-Sunyer, F. X. et al. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA 295, 761–775 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Curioni, C. & André, C. Rimonabant for overweight or obesity. Cochrane Database Syst. Rev. CD006162 (2006).

  115. Christensen, R., Kristensen, P. K., Bartels, E. M., Bliddal, H. & Astrup, A. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 370, 1706–1713 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Nathan, P. J., O'Neill, B. V., Napolitano, A. & Bullmore, E. T. Neuropsychiatric adverse effects of centrally acting antiobesity drugs. CNS Neurosci. Ther. 17, 490–505 (2010).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  117. Addy, C. et al. Multiple-dose pharmacokinetics, pharmacodynamics, and safety of taranabant, a novel selective cannabinoid-1 receptor inverse agonist, in healthy male volunteers. J. Clin. Pharmacol. 48, 734–744 (2008).

    Article  CAS  PubMed  Google Scholar 

  118. Addy, C. et al. Safety, tolerability, pharmacokinetics, and pharmacodynamic properties of taranabant, a novel selective cannabinoid-1 receptor inverse agonist, for the treatment of obesity: results from a double-blind, placebo-controlled, single oral dose study in healthy volunteers. J. Clin. Pharmacol. 48, 418–427 (2008).

    Article  CAS  PubMed  Google Scholar 

  119. Wadden, T. A. et al. A randomized trial of lifestyle modification and taranabant for maintaining weight loss achieved with a low-calorie diet. Obesity (Silver Spring) 18, 2301–2310 (2010).

    Article  PubMed Central  Google Scholar 

  120. Proietto, J. et al. A clinical trial assessing the safety and efficacy of the CB1R inverse agonist taranabant in obese and overweight patients: low-dose study. Int. J. Obes. (Lond.) 34, 1243–1254 (2010).

    Article  CAS  Google Scholar 

  121. Kipnes, M. S. et al. A one-year study to assess the safety and efficacy of the CB1R inverse agonist taranabant in overweight and obese patients with type 2 diabetes. Diabetes Obes. Metab. 12, 517–531 (2010).

    Article  CAS  PubMed  Google Scholar 

  122. Aronne, L. J. et al. A clinical trial assessing the safety and efficacy of taranabant, a CB1R inverse agonist, in obese and overweight patients: a high-dose study. Int. J. Obes. (Lond.) 34, 919–935 (2010).

    Article  CAS  Google Scholar 

  123. Koch, L. Obesity: taranabant no longer developed as an antiobesity agent. Nature Rev. Endocrinol. 6, 300 (2010).

    Article  Google Scholar 

  124. Griffith, D. A. et al. Discovery of 1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-4-ethylaminopiperidine-4-carboxylic acid amide hydrochloride (CP-945598), a novel, potent, and selective cannabinoid type 1 receptor antagonist. J. Med. Chem. 52, 234–237 (2009).

    Article  CAS  PubMed  Google Scholar 

  125. Hadcock, J. R. et al. In vitro and in vivo pharmacology of CP-945598, a potent and selective cannabinoid CB1 receptor antagonist for the management of obesity. Biochem. Biophys. Res. Commun. 394, 366–371 (2010).

    Article  CAS  PubMed  Google Scholar 

  126. Aronne, L. J. et al. Efficacy and safety of CP-945598, a selective cannabinoid CB1 receptor antagonist, on weight loss and maintenance. Obesity 19, 1404–1414 (2011).

    Article  CAS  PubMed  Google Scholar 

  127. Nogueiras, R. et al. Peripheral, but not central, CB1 antagonism provides food intake-independent metabolic benefits in diet-induced obese rats. Diabetes 57, 2977–2991 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Son, M.-H. et al. Peripherally acting CB1-receptor antagonist: the relative importance of central and peripheral CB1 receptors in adiposity control. Int. J. Obes. (Lond.) 34, 547–556 (2010).

    Article  CAS  Google Scholar 

  129. Quarta, C., Mazza, R., Obici, S., Pasquali, R. & Pagotto, U. Energy balance regulation by endocannabinoids at central and peripheral levels. Trends Mol. Med. 17, 518–526 (2011).

    Article  CAS  PubMed  Google Scholar 

  130. Heisler, L. K. et al. Central serotonin and melanocortin pathways regulating energy homeostasis. Ann. NY Acad. Sci. 994, 169–174 (2003).

    Article  CAS  PubMed  Google Scholar 

  131. Smith, B. M. et al. Discovery and structure–activity relationship of (1R)-8-chloro-2, 3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity. J. Med. Chem. 51, 305–313 (2008).

    Article  CAS  PubMed  Google Scholar 

  132. Thomsen, W. J. et al. Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization. J. Pharmacol. Exp. Ther. 325, 577–587 (2008).

    Article  CAS  PubMed  Google Scholar 

  133. Smith, S. R. et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N. Engl. J. Med. 363, 245–256 (2010).

    Article  CAS  PubMed  Google Scholar 

  134. Fidler, M. C. et al. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J. Clin. Endocrinol. Metab. 96, 3067–3077 (2011).

    Article  CAS  PubMed  Google Scholar 

  135. Arena Pharmaceuticals. Lorcaserin Phase 3 Clinical Trial in Patients with Type 2 Diabetes Shows Statistically Significant Weight Loss. Arena Pharmaceuticals [online] (2010).

  136. O'Neil, P. M. et al. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study. Obesity (Silver Spring) 16 Mar 2012 (doi:10.1038/oby.2012.66).

    Article  CAS  PubMed  Google Scholar 

  137. Clemett, D. A., Punhani, T., Duxon, M. S., Blackburn, T. P. & Fone, K. C. Immunohistochemical localisation of the 5-HT2C receptor protein in the rat CNS. Neuropharmacology 39, 123–132 (2000).

    Article  CAS  PubMed  Google Scholar 

  138. Abramowski, D., Rigo, M., Duc, D., Hoyer, D. & Staufenbiel, M. Localization of the 5-hydroxytryptamine 2C receptor protein in human and rat brain using specific antisera. Neuropharmacology 34, 1635–1645 (1995).

    Article  CAS  PubMed  Google Scholar 

  139. Abramowski, D. & Staufenbiel, M. Identification of the 5-hydroxytryptamine 2C receptor as a 60-kDa N-glycosylated protein in choroid plexus and hippocampus. J. Neurochem. 65, 782–790 (1995).

    Article  CAS  PubMed  Google Scholar 

  140. Sharma, A., Punhani, T. & Fone, K. C. Distribution of the 5-hydroxytryptamine 2C receptor protein in adult rat brain and spinal cord determined using a receptor-directed antibody: effect of 5,7-dihydroxytryptamine. Synapse 27, 45–56 (1997).

    Article  CAS  PubMed  Google Scholar 

  141. Pollack, A. Panel recommends more testing for obesity drugs. The New York Times [online] (2012).

  142. Ledford, H. Heart studies needed for obesity drugs, FDA advisers say. Nature [online] (2012).

  143. Gadde, K. M. et al. Bupropion for weight loss: an investigation of efficacy and tolerability in overweight and obese women. Obes. Res. 9, 544–551 (2001).

    Article  CAS  PubMed  Google Scholar 

  144. Anderson, J. W. et al. Bupropion SR enhances weight loss: a 48-week double-blind, placebo- controlled trial. Obes. Res. 10, 633–641 (2002).

    Article  CAS  PubMed  Google Scholar 

  145. Greenway, F. L. et al. Rational design of a combination medication for the treatment of obesity. Obesity 17, 30–39 (2009).

    Article  CAS  PubMed  Google Scholar 

  146. Wellman, P. J. Norepinephrine and the control of food intake. Nutrition 16, 837–842 (2000).

    Article  CAS  PubMed  Google Scholar 

  147. Hnasko, T. S., Szczypka, M. S., Alaynick, W. A., During, M. J. & Palmiter, R. D. A role for dopamine in feeding responses produced by orexigenic agents. Brain Res. 1023, 309–318 (2004).

    Article  CAS  PubMed  Google Scholar 

  148. Sotak, B. N., Hnasko, T. S., Robinson, S., Kremer, E. J. & Palmiter, R. D. Dysregulation of dopamine signaling in the dorsal striatum inhibits feeding. Brain Res. 1061, 88–96 (2005).

    Article  CAS  PubMed  Google Scholar 

  149. Hnasko, T. S. et al. Cre recombinase-mediated restoration of nigrostriatal dopamine in dopamine-deficient mice reverses hypophagia and bradykinesia. Proc. Natl Acad. Sci. USA 103, 8858–8863 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Domingos, A. I. et al. Leptin regulates the reward value of nutrient. Nature Neurosci. 14, 1562–1568 (2011).

    Article  CAS  PubMed  Google Scholar 

  151. Ornellas, T. & Chavez, B. Naltrexone SR/Bupropion SR (Contrave): a new approach to weight loss in obese adults. P T 36, 255–262 (2011).

    PubMed  PubMed Central  Google Scholar 

  152. Wadden, T. A. et al. Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: the COR-BMOD trial. Obesity 19, 110–120 (2011).

    Article  CAS  PubMed  Google Scholar 

  153. Greenway, F. L. et al. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 376, 595–605 (2010).

    Article  CAS  PubMed  Google Scholar 

  154. Orexigen Therapeutics. Orexigen and FDA Identify a Clear and Feasible Path to Approval for Contrave. Orexigen [online] (2011).

  155. Ledford, H. Slim spoils for obesity drugs. Nature 468, 878 (2010).

    Article  CAS  PubMed  Google Scholar 

  156. Rothman, R. B. & Baumann, M. H. Appetite suppressants, cardiac valve disease and combination pharmacotherapy. Am. J. Ther. 16, 354–364 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Wilding, J., Van Gaal, L., Rissanen, A., Vercruysse, F. & Fitchet, M. A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects. Int. J. Obes. 28, 1399–1410 (2004).

    Article  CAS  Google Scholar 

  158. Bray, G. A. et al. A 6-month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in obesity. Obes. Res. 11, 722–733 (2003).

    Article  CAS  PubMed  Google Scholar 

  159. Tonstad, S. et al. Efficacy and safety of topiramate in the treatment of obese subjects with essential hypertension. Am. J. Cardiol. 96, 243–251 (2005).

    Article  CAS  PubMed  Google Scholar 

  160. Gadde, K. M. et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet 377, 1341–1352 (2011).

    Article  CAS  PubMed  Google Scholar 

  161. Allison, D. B. et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity 20, 330–342 (2011).

    Article  PubMed  CAS  Google Scholar 

  162. Katz, A. Modulation of glucose transport in skeletal muscle by reactive oxygen species. J. Appl. Physiol. 102, 1671–1676 (2007).

    Article  CAS  PubMed  Google Scholar 

  163. Ritchie, R. H. & Delbridge, L. M. Cardiac hypertrophy, substrate utilization and metabolic remodelling: cause or effect? Clin. Exp. Pharmacol. Physiol. 33, 159–166 (2006).

    Article  CAS  PubMed  Google Scholar 

  164. Lopaschuk, G. D. & Jaswal, J. S. Energy metabolic phenotype of the cardiomyocyte during development, differentiation, and postnatal maturation. J. Cardiovasc. Pharmacol. 56, 130–140 (2010).

    Article  CAS  PubMed  Google Scholar 

  165. Augustus, A. S. et al. Loss of lipoprotein lipase-derived fatty acids leads to increased cardiac glucose metabolism and heart dysfunction. J. Biol. Chem. 281, 8716–8723 (2006).

    Article  CAS  PubMed  Google Scholar 

  166. Gupte, S. A. et al. Glucose-6-phosphate dehydrogenase-derived NADPH fuels superoxide production in the failing heart. J. Mol. Cell. Cardiol. 41, 340–349 (2006).

    Article  CAS  PubMed  Google Scholar 

  167. Gupte, R. S. et al. Upregulation of glucose-6-phosphate dehydrogenase and NAD(P)H oxidase activity increases oxidative stress in failing human heart. J. Card. Fail. 13, 497–506 (2007).

    Article  CAS  PubMed  Google Scholar 

  168. Stanley, W. C., Recchia, F. A. & Lopaschuk, G. D. Myocardial substrate metabolism in the normal and failing heart. Physiol. Rev. 85, 1093–1129 (2005).

    Article  CAS  PubMed  Google Scholar 

  169. Sharma, N. et al. High fructose diet increases mortality in hypertensive rats compared to a complex carbohydrate or high fat diet. Am. J. Hypertens. 20, 403–409 (2007).

    Article  CAS  PubMed  Google Scholar 

  170. Lee, C. et al. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci. Transl. Med. 4, 124ra127 (2012).

    Article  Google Scholar 

  171. Lee, C. & Longo, V. D. Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients. Oncogene 30, 3305–3316 (2011).

    Article  CAS  PubMed  Google Scholar 

  172. Raffaghello, L. et al. Fasting and differential chemotherapy protection in patients. Cell Cycle 9, 4474–4476 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Safdie, F. M. et al. Fasting and cancer treatment in humans: a case series report. Aging (Albany NY) 1, 988–1007 (2009).

    Article  Google Scholar 

  174. Raffaghello, L. et al. Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proc. Natl Acad. Sci. USA 105, 8215–8220 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Liao, C. Y., Rikke, B. A., Johnson, T. E., Diaz, V. & Nelson, J. F. Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. Aging Cell 9, 92–95 (2010).

    Article  CAS  PubMed  Google Scholar 

  176. Fontana, L., Klein, S. & Holloszy, J. O. Long-term low-protein, low-calorie diet and endurance exercise modulate metabolic factors associated with cancer risk. Am. J. Clin. Nutr. 84, 1456–1462 (2006).

    Article  CAS  PubMed  Google Scholar 

  177. Fontana, L., Klein, S. & Holloszy, J. O. Effects of long-term calorie restriction and endurance exercise on glucose tolerance, insulin action, and adipokine production. Age (Dordr.) 32, 97–108 (2010).

    Article  CAS  Google Scholar 

  178. Fontana, L. et al. Calorie restriction or exercise: effects on coronary heart disease risk factors. A randomized, controlled trial. Am. J. Physiol. Endocrinol. Metab. 293, e197–e202 (2007).

    Article  CAS  PubMed  Google Scholar 

  179. Riordan, M. M. et al. The effects of caloric restriction- and exercise-induced weight loss on left ventricular diastolic function. Am. J. Physiol. Heart Circ. Physiol. 294, H1174–H1182 (2008).

    Article  CAS  PubMed  Google Scholar 

  180. Villareal, D. T. et al. Bone mineral density response to caloric restriction-induced weight loss or exercise-induced weight loss: a randomized controlled trial. Arch. Int. Med. 166, 2502–2510 (2006).

    Article  Google Scholar 

  181. Villareal, D. T. et al. Reduced bone mineral density is not associated with significantly reduced bone quality in men and women practicing long-term calorie restriction with adequate nutrition. Aging Cell 10, 96–102 (2011).

    Article  CAS  PubMed  Google Scholar 

  182. MacDonald, L., Radler, M., Paolini, A. G. & Kent, S. Calorie restriction attenuates LPS-induced sickness behavior and shifts hypothalamic signaling pathways to an anti-inflammatory bias. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R172–R184 (2011).

    Article  CAS  PubMed  Google Scholar 

  183. Milanski, M. et al. Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J. Neurosci. 29, 359–370 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Fleischman, A., Shoelson, S. E., Bernier, R. & Goldfine, A. B. Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care 31, 289–294 (2008).

    Article  CAS  PubMed  Google Scholar 

  185. Baur, J. A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342 (2006). Describes the beneficial effects in mice of chronic resveratrol administration for the treatment of metabolic disorders.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122 (2006).

    Article  CAS  PubMed  Google Scholar 

  187. Pearson, K. J. et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab. 8, 157–168 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Timmers, S. et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 14, 612–622 (2011).

    Article  CAS  PubMed  Google Scholar 

  189. Ganjam, G. K., Dimova, E. Y., Unterman, T. G. & Kietzmann, T. FoxO1 and HNF-4 are involved in regulation of hepatic glucokinase gene expression by resveratrol. J. Biol. Chem. 284, 30783–30797 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Bickenbach, K. A. et al. Resveratrol is an effective inducer of CArG-driven TNF-α gene therapy. Cancer Gene Ther. 15, 133–139 (2008).

    Article  CAS  PubMed  Google Scholar 

  191. Park, C. E. et al. Resveratrol stimulates glucose transport in C2C12 myotubes by activating AMP-activated protein kinase. Exp. Mol. Med. 39, 222–229 (2007).

    Article  CAS  PubMed  Google Scholar 

  192. Dasgupta, B. & Milbrandt, J. Resveratrol stimulates AMP kinase activity in neurons. Proc. Natl Acad. Sci. USA 104, 7217–7222 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Andrews, Z. B. et al. Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism. J. Neurosci. 29, 14057–14065 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. He, C. et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481, 511–515 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Sakamoto, K., Goransson, O., Hardie, D. G. & Alessi, D. R. Activity of LKB1 and AMPK-related kinases in skeletal muscle: effects of contraction, phenformin, and AICAR. Am. J. Physiol. Endocrinol. Metab. 287, e310–e317 (2004).

    Article  CAS  PubMed  Google Scholar 

  196. Narkar, V. A. et al. AMPK and PPARδ agonists are exercise mimetics. Cell 134, 405–415 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Diano, S. et al. Ghrelin controls hippocampal spine synapse density and memory performance. Nature Neurosci. 9, 381–388 (2006).

    Article  CAS  PubMed  Google Scholar 

  198. Abizaid, A. et al. Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J. Clin. Invest. 116, 3229–3239 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Perry, M. L. et al. Leptin promotes dopamine transporter and tyrosine hydroxylase activity in the nucleus accumbens of Sprague-Dawley rats. J. Neurochem. 114, 666–674 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Opland, D. M., Leinninger, G. M. & Myers, M. G. Modulation of the mesolimbic dopamine system by leptin. Brain Res. 1350, 65–70 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Fulton, S. et al. Leptin regulation of the mesoaccumbens dopamine pathway. Neuron 51, 811–822 (2006).

    Article  CAS  PubMed  Google Scholar 

  202. Hommel, J. D. et al. Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron 51, 801–810 (2006).

    Article  CAS  PubMed  Google Scholar 

  203. Muller, A. P. et al. Exercise increases insulin signaling in the hippocampus: physiological effects and pharmacological impact of intracerebroventricular insulin administration in mice. Hippocampus 21, 1082–1092 (2011).

    Article  CAS  PubMed  Google Scholar 

  204. Greenfield, J. R. et al. Modulation of blood pressure by central melanocortinergic pathways. N. Engl. J. Med. 360, 44–52 (2009).

    Article  CAS  PubMed  Google Scholar 

  205. Greenfield, J. R. Melanocortin signalling and the regulation of blood pressure in human obesity. J. Neuroendocrinol. 23, 186–193 (2011).

    Article  CAS  PubMed  Google Scholar 

  206. Kolonin, M. G., Saha, P. K., Chan, L., Pasqualini, R. & Arap, W. Reversal of obesity by targeted ablation of adipose tissue. Nature Med. 10, 625–632 (2004).

    Article  CAS  PubMed  Google Scholar 

  207. Barnhart, K. F. et al. A peptidomimetic targeting white fat causes weight loss and improved insulin resistance in obese monkeys. Sci. Transl. Med. 3, 108ra112 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  208. Lijnen, H. R., Frederix, L. & Van Hoef, B. Fumagillin reduces adipose tissue formation in murine models of nutritionally induced obesity. Obesity 18, 2241–2246 (2010).

    Article  CAS  PubMed  Google Scholar 

  209. Scroyen, I., Christiaens, V. & Lijnen, H. R. Effect of fumagillin on adipocyte differentiation and adipogenesis. Biochim. Biophys. Acta 1800, 425–429 (2010).

    Article  CAS  PubMed  Google Scholar 

  210. Kim, D. H., Woods, S. C. & Seeley, R. J. Peptide designed to elicit apoptosis in adipose tissue endothelium reduces food intake and body weight. Diabetes 59, 907–915 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).

    Article  CAS  PubMed  Google Scholar 

  212. Richard, D. & Picard, F. Brown fat biology and thermogenesis. Frontiers Biosci. 16, 1233–1260 (2011).

    Article  CAS  Google Scholar 

  213. Kim, E. B. et al. Genome sequencing reveals insights into physiology and longevity of the naked mole rat. Nature 479, 223–227 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Cypess, A. M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009). Describes the presence of BAT in adult humans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Ouellet, V. et al. Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J. Clin. Invest. 122, 545–552 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  216. Bartelt, A. et al. Brown adipose tissue activity controls triglyceride clearance. Nature Med. 17, 200–205 (2011).

    Article  CAS  PubMed  Google Scholar 

  217. Bostrom, P. et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463–468 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  218. Karelis, A. D. et al. The metabolically healthy but obese individual presents a favorable inflammation profile. J. Clin. Endocrinol. Metab. 90, 4145–4150 (2005).

    Article  CAS  PubMed  Google Scholar 

  219. Brochu, M. et al. What are the physical characteristics associated with a normal metabolic profile despite a high level of obesity in postmenopausal women? J. Clin. Endocrinol. Metab. 86, 1020–1025 (2001).

    CAS  PubMed  Google Scholar 

  220. Arnlov, J., Ingelsson, E., Sundstrom, J. & Lind, L. Impact of body mass index and the metabolic syndrome on the risk of cardiovascular disease and death in middle-aged men. Circulation 121, 230–236 (2010).

    Article  PubMed  Google Scholar 

  221. Arnlov, J., Sundstrom, J., Ingelsson, E. & Lind, L. Impact of BMI and the metabolic syndrome on the risk of diabetes in middle-aged men. Diabetes Care 34, 61–65 (2011).

    Article  PubMed  CAS  Google Scholar 

  222. Appel, L. J. et al. Comparative effectiveness of weight-loss interventions in clinical practice. N. Engl. J. Med. 365, 1959–1968 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Wadden, T. A. et al. A two-year randomized trial of obesity treatment in primary care practice. N. Engl. J. Med. 365, 1969–1979 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Yaswen, L., Diehl, N., Brennan, M. B. & Hochgeschwender, U. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nature Med. 5, 1066–1070 (1999).

    Article  CAS  PubMed  Google Scholar 

  225. Yen, T. T., Gill, A. M., Frigeri, L. G., Barsh, G. S. & Wolff, G. L. Obesity, diabetes, and neoplasia in yellow Avy/– mice: ectopic expression of the agouti gene. FASEB J. 8, 479–488 (1994).

    Article  CAS  PubMed  Google Scholar 

  226. Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141 (1997).

    Article  CAS  PubMed  Google Scholar 

  227. 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 

  228. Krude, H. et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nature Genet. 19, 155–157 (1998).

    Article  CAS  PubMed  Google Scholar 

  229. Clément, K. et al. Unexpected endocrine features and normal pigmentation in a young adult patient carrying a novel homozygous mutation in the POMC gene. J. Clin. Endocrinol. Metab. 93, 4955–4962 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  230. Vaisse, C., Clement, K., Guy-Grand, B. & Froguel, P. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nature Genet. 20, 113–114 (1998).

    Article  CAS  PubMed  Google Scholar 

  231. Yeo, G. S. et al. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nature Genet. 20, 111–112 (1998).

    Article  CAS  PubMed  Google Scholar 

  232. 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  PubMed Central  Google Scholar 

  233. Vaisse, C. et al. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J. Clin. Invest. 106, 253–262 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Farooqi, I. S. et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N. Engl. J. Med. 348, 1085–1095 (2003). A comprehensive description of a series of mutations in the MC4R gene, which is involved in obesity syndromes in humans.

    Article  CAS  PubMed  Google Scholar 

  235. Branson, R. et al. Binge eating as a major phenotype of melanocortin 4 receptor gene mutations. N. Engl. J. Med. 348, 1096–1103 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  237. Wiedmer, P. et al. The HPA axis modulates the CNS melanocortin control of liver triacylglyceride metabolism. Physiol. Behav. 105, 791–799 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  238. Perez-Tilve, D. et al. Melanocortin signaling in the CNS directly regulates circulating cholesterol. Nature Neurosci. 13, 877–882 (2010).

    Article  CAS  PubMed  Google Scholar 

  239. Vella, K. R. et al. NPY and MC4R signaling regulate thyroid hormone levels during fasting through both central and peripheral pathways. Cell Metab. 14, 780–790 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Preston, E. et al. Central neuropeptide Y infusion and melanocortin 4 receptor antagonism inhibit thyrotropic function by divergent pathways. Neuropeptides 45, 407–415 (2011).

    Article  CAS  PubMed  Google Scholar 

  241. Tong, Q., Ye, C. P., Jones, J. E., Elmquist, J. K. & Lowell, B. B. Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nature Neurosci. 11, 998–1000 (2008).

    Article  CAS  PubMed  Google Scholar 

  242. Wu, Q. & Palmiter, R. D. GABAergic signaling by AgRP neurons prevents anorexia via a melanocortin-independent mechanism. Eur. J. Pharmacol. 660, 21–27 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Wu, Q., Howell, M. P., Cowley, M. A. & Palmiter, R. D. Starvation after AgRP neuron ablation is independent of melanocortin signaling. Proc. Natl Acad. Sci. USA 105, 2687–2692 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Grandison, L. & Guidotti, A. Stimulation of food intake by muscimol and β endorphin. Neuropharmacology 16, 533–536 (1977).

    Article  CAS  PubMed  Google Scholar 

  245. Kelly, J., Alheid, G. F., Newberg, A. & Grossman, S. P. GABA stimulation and blockade in the hypothalamus and midbrain: effects on feeding and locomotor activity. Pharmacol. Biochem. Behav. 7, 537–541 (1977).

    Article  CAS  PubMed  Google Scholar 

  246. Przewlocka, B., Stala, L. & Scheel-Kruger, J. Evidence that GABA in the nucleus dorsalis raphe induces stimulation of locomotor activity and eating behavior. Life Sci. 25, 937–945 (1979).

    Article  CAS  PubMed  Google Scholar 

  247. Kelly, J., Rothstein, J. & Grossman, S. P. GABA and hypothalamic feeding systems. I. Topographic analysis of the effects of microinjections of muscimol. Physiol. Behav. 23, 1123–1134 (1979).

    Article  CAS  PubMed  Google Scholar 

  248. Wu, Q., Clark, M. S. & Palmiter, R. D. Deciphering a neuronal circuit that mediates appetite. Nature 483, 594–597 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Kojima, M. et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402, 656–660 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  251. Cowley, M. A. et al. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37, 649–661 (2003).

    Article  CAS  PubMed  Google Scholar 

  252. Carlini, V. P. et al. Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin. Biochem. Biophys. Res. Commun. 313, 635–641 (2004).

    Article  CAS  PubMed  Google Scholar 

  253. Malik, S., McGlone, F., Bedrossian, D. & Dagher, A. Ghrelin modulates brain activity in areas that control appetitive behavior. Cell Metab. 7, 400–409 (2008).

    Article  CAS  PubMed  Google Scholar 

  254. Yang, Y., Atasoy, D., Su, H. H. & Sternson, S. M. Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell 146, 992–1003 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Dietrich, M. O. & Horvath, T. L. Synaptic plasticity of feeding circuits: hormones and hysteresis. Cell 146, 863–865 (2011).

    Article  CAS  PubMed  Google Scholar 

  256. Kohno, D., Sone, H., Minokoshi, Y. & Yada, T. Ghrelin raises [Ca2+]i via AMPK in hypothalamic arcuate nucleus NPY neurons. Biochem. Biophys. Res. Commun. 366, 388–392 (2008).

    Article  CAS  PubMed  Google Scholar 

  257. Szczypka, M. S. et al. Dopamine production in the caudate putamen restores feeding in dopamine-deficient mice. Neuron 30, 819–828 (2001).

    Article  CAS  PubMed  Google Scholar 

  258. Szczypka, M. S. et al. Feeding behavior in dopamine-deficient mice. Proc. Natl Acad. Sci. USA 96, 12138–12143 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Szczypka, M. S., Rainey, M. A. & Palmiter, R. D. Dopamine is required for hyperphagia in Lepob/ob mice. Nature Genet. 25, 102–104 (2000).

    Article  CAS  PubMed  Google Scholar 

  260. Morrison, C. D. Leptin signaling in brain: a link between nutrition and cognition? Biochim. Biophys. Acta 1792, 401–408 (2009).

    Article  CAS  PubMed  Google Scholar 

  261. Farooqi, I. S. et al. Leptin regulates striatal regions and human eating behavior. Science 317, 1355 (2007).

    Article  CAS  PubMed  Google Scholar 

  262. Batterham, R. L. et al. PYY modulation of cortical and hypothalamic brain areas predicts feeding behaviour in humans. Nature 450, 106–109 (2007).

    Article  CAS  PubMed  Google Scholar 

  263. Ren, H. et al. FoxO1 target Gpr17 activates AgRP neurons to regulate food intake. Cell 149, 1314–1326 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Atasoy, D., Betley, J. N., Su, H. H. & Sternson, S. M. Deconstruction of a neural circuit for hunger. Nature 11 July 2012 (doi:10.1038/nature11270).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Dietrich, M. O. et al. AgRP neurons regulate development of dopamine neuronal plasticity and nonfood-associated behaviors. Nature Neurosci. 24 June 2012 (doi:10.1038/nn.3147).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The preparation of this manuscript was supported by a US National Institutes of Health Director's Pioneer Award to T.L.M. M.O.D. was partially supported by CNPq-Brazil.

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IUPHAR Database of Receptors and Ion Channels

Glossary

Overnutrition

A positive energy balance in which the absorption of energy surpasses its metabolism by the body; that is, intake is higher than expenditure.

Appetite

A complex desire to fulfil the body's need with something, usually with food (perceived as hunger).

Food cravings

Intense desires to ingest specific types of food. These desires are not necessarily linked to hunger.

Satiety

A state in which the individual is fed and/or gratified with the amount of energy ingested.

Mnemonic functions

Cognitive functions of the brain that are involved in memory processes.

Endoplasmic reticulum (ER) stress

A state in an organelle that occurs owing to disturbances in metabolic homeostasis, which lead to an accumulation of unfolded proteins and consequent organelle dysfunction.

Peroxisome

An organelle found in virtually every mammalian cell that is mainly involved in the catabolism of very long-chain fatty acids.

Paresthaesia

The sensation of numbness or tingling on the skin, usually in the extremities (fingers and toes) without any apparent physical problem.

Nephrolithiasis

A common disease characterized by the presence of calculi in the kidneys that occurs mainly in men.

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Dietrich, M., Horvath, T. Limitations in anti-obesity drug development: the critical role of hunger-promoting neurons. Nat Rev Drug Discov 11, 675–691 (2012). https://doi.org/10.1038/nrd3739

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