Mutations in ligands and receptors of the leptin-melanocortin pathway that lead to obesity

Nature Clinical Practice Endocrinology and Metabolism

Volumn 4, Issue 10, 2008, Pages 569-577

  Farooqi, I Sadaf ^a   O'Rahilly, Stephen ^a  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

Author keywords

Genetics; Leptin; Melanocortin; Mutation; Obesity

Indexed keywords

BRAIN DERIVED NEUROTROPHIC FACTOR; BRAIN DERIVED NEUROTROPHIC FACTOR RECEPTOR; LEPTIN; LEPTIN RECEPTOR; MELANOCORTIN; PROOPIOMELANOCORTIN; PROPROTEIN CONVERTASE 1;

BODY WEIGHT; FOOD INTAKE; GENE MUTATION; GENETIC DISORDER; HORMONE DEFICIENCY; HUMAN; LEPTIN DEFICIENCY; LEPTIN RECEPTOR DEFICIENCY; MELANOCORTIN 4 RECEPTOR DEFICIENCY; MONOGENIC DISORDER; NONHUMAN; OBESITY; PHENOTYPE; PREVALENCE; PRIORITY JOURNAL; PROOPIOMELANOCORTIN DEFICIENCY; PROPROTEIN CONVERTASE 1 DEFICIENCY; PROTEIN DEFECT; REVIEW; SIGNAL TRANSDUCTION;

DRUG RESISTANCE; GENETIC PREDISPOSITION TO DISEASE; HUMANS; LEPTIN; LIGANDS; MELANOCORTINS; MODELS, BIOLOGICAL; MUTATION; OBESITY; PRO-OPIOMELANOCORTIN; RECEPTORS, LEPTIN; RECEPTORS, MELANOCORTIN; SIGNAL TRANSDUCTION; SYNDROME;

EID: 52449123919     PISSN: 17458366     EISSN: 17458374     Source Type: Journal    
DOI: 10.1038/ncpendmet0966     Document Type: Review

References (66)

1. Barsh GS et al. (2000) Genetics of body-weight regulation. Nature 404: 644-651
2. Frayling TM et al. (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316: 889-894
3. Dina C et al. (2007) Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 39: 724-726
4. Hinney A et al. (2007) Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants. PLoS ONE 2: e1361
5. Gerken T et al. (2007) The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 318: 1469-1472
6. Stratigopoulos G et al. (2008) Regulation of Fto/Ftm gene expression in mice and humans. Am J Physiol Regul Integr Comp Physiol 294: R1185-R1196
7. Wardle J et al. (2008) Obesity-associated genetic variation in FTO is associated with diminished satiety. J Clin Endocrinol Metab [doi:10.1210/jc.2008-0472]
8. Berentzen T et al. (2008) Lack of association of fatness-related FTO gene variants with energy expenditure or physical activity. J Clin Endocrinol Metab 93: 2904-2908
9. Loos RJ et al. (2008) Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 40: 768-775
10. Zhang Y et al. (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372: 425-432
11. Maffei M et al. (1995) Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1: 1155-1161
12. Ahima RS et al. (1996) Role of leptin in the neuroendocrine response to fasting. Nature 382: 250-252
13. Elmquist JK et al. (1998) Distributions of leptin receptor mRNA isoforms in the rat brain. J Comp Neurol 395: 535-547
14. Tartaglia LA (1997) The leptin receptor. J Biol Chem 272: 6093-6096
15. Myers MG et al. (2008) Mechanisms of leptin action and leptin resistance. Annu Rev Physiol 70: 537-556
16. Bates SH et al. (2003) STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 421: 856-859
17. Schwartz MW et al. (2000) Central nervous system control of food intake. Nature 404: 661-671
18. Pritchard LE et al. (2002) Pro-opiomelanocortin processing in the hypothalamus: impact on melanocortin signalling and obesity. J Endocrinol 172: 411-421
19. Montague CT et al. (1997) Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387: 903-908
20. Gibson WT et al. (2004) Congenital leptin deficiency due to homozygosity for the Delta133G mutation: report of another case and evaluation of response to four years of leptin therapy. J Clin Endocrinol Metab 89: 4821-4826
21. Strobel A et al. (1998) A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 18: 213-215
22. Ozata M et al. (1999) Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab 84: 3686-3695
23. Farooqi IS et al. (2007) Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med 356: 237-247
24. Farooqi IS et al. (2001) Partial leptin deficiency and human adiposity. Nature 414: 34-35
25. Lahlou N et al. (2000) Soluble leptin receptor in serum of subjects with complete resistance to leptin: relation to fat mass. Diabetes 49: 1347-1352
26. Farooqi IS et al. (1999) Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 341: 879-884
27. Farooqi IS et al. (2007) Leptin regulates striatal regions and human eating behavior. Science 317: 1355
28. Clément K et al. (1998) A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392: 398-401
29. Farooqi IS et al. (2002) Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 110: 1093-1103
30. Licinio J et al. (2004) Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci USA 101: 4531-4536
31. Heymsfield SB et al. (1999) Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 282: 1568-1575
32. Howard JK et al. (2004) Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat Med 10: 734-738
33. Kaszubska W et al. (2002) Protein tyrosine phosphatase 1B negatively regulates leptin signaling in a hypothalamic cell line. Mol Cell Endocrinol 195: 109-118
34. Klaman LD et al. (2000) Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol Cell Biol 20: 5479-5489
35. Cone RD (1999) The central melanocortin system and energy homeostasis. Trends Endocrinol Metab 10: 211-216
36. Coll AP et al. (2004) Proopiomelanocortin and energy balance: insights from human and murine genetics. J Clin Endocrinol Metab 89: 2557-2562
37. Farooqi IS et al. (2000) Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest 106: 271-279
38. Huszar D et al. (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88: 131-141
39. Butler AA et al. (2000) A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology 141: 3518-3521
40. Lee YS et al. (2002) A novel melanocortin 3 receptor gene (MC3R) mutation associated with severe obesity. J Clin Endocrinol Metab 87: 1423-1426
41. Krude H et al. (1998) Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19: 155-157
42. Krude H et al. (2003) Obesity due to proopiomelanocortin deficiency: three new cases and treatment trials with thyroid hormone and ACTH4-10. J Clin Endocrinol Metab 88: 4633-4640
43. Farooqi IS et al. (2006) Heterozygosity for a POMC-null mutation and increased obesity risk in humans. Diabetes 55: 2549-2553
44. Challis BG et al. (2002) A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism. Hum Mol Genet 11: 1997-2004
45. Echwald SM et al. (1999) Mutational analysis of the proopiomelanocortin gene in Caucasians with early onset obesity. Int J Obes Relat Metab Disord 23: 293-298
46. Lee YS et al. (2006) A POMC variant implicates beta-melanocyte-stimulating hormone in the control of human energy balance. Cell Metab 3: 135-140
47. Biebermann H et al. (2006) A role for beta-melanocyte-stimulating hormone in human body-weight regulation. Cell Metab 3: 141-146
48. Jackson RS et al. (2003) Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. J Clin Invest 112: 1550-1560
49. Jackson RS et al. (1997) Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 16: 303-306
50. Farooqi IS et al. (2007) Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3. J Clin Endocrinol Metab 92: 3369-3373
51. Pogozheva ID et al. (2005) Interactions of human melanocortin 4 receptor with nonpeptide and peptide agonists. Biochemistry 44: 11329-11341
52. Farooqi IS et al. (2003) Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 348: 1085-1095
53. Alharbi KK et al. (2007) Prevalence and functionality of paucimorphic and private MC4R mutations in a large, unselected European British population, scanned by meltMADGE. Hum Mutat 28: 294-302
54. Vaisse C et al. (2000) Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest 106: 253-262
55. Stutzmann F et al. (2008) Prevalence of MC4R deficiency in European population and their age-dependant penetrance in multi-generational pedigrees. Diabetes [doi:10.2337/db08-0153]
56. Nogueiras R et al. (2007) The central melanocortin system directly controls peripheral lipid metabolism. J Clin Invest 117: 3475-3488
57. Yeo GS et al. (2003) Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms. Hum Mol Genet 12: 561-574
58. Lubrano-Berthelier C et al. (2006) Melanocortin 4 receptor mutations in a large cohort of severely obese adults: prevalence, functional classification, genotype-phenotype relationship, and lack of association with binge eating. J Clin Endocrinol Metab 91: 1811-1818
59. Jones KR et al. (1994) Targeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development. Cell 76: 989-999
60. Kernie SG et al. (2000) BDNF regulates eating behavior and locomotor activity in mice. EMBO J 19: 1290-1300
61. Xu B et al. (2003) Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci 6: 736-742
62. Yeo GS et al. (2004) A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nat Neurosci 7: 1187-1189
63. Gray J et al. (2006) Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. Diabetes 55: 3366-3371
64. Otvos L Jr et al. (2008) Development of a pharmacologically improved peptide agonist of the leptin receptor. Biochim Biophys Acta [doi:10.1016/j.bbamcr.2008.05.007]
65. Hsiung HM et al. (2005) A novel and selective beta-melanocyte- stimulating hormone-derived peptide agonist for melanocortin 4 receptor potently decreased food intake and body weight gain in diet-induced obese rats. Endocrinology 146: 5257-5266
66. Emmerson PJ et al. (2007) Melanocortin-4 receptor agonists for the treatment of obesity. Curr Top Med Chem 7: 1121-1130