Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

Abstract

Obesity is associated with increased morbidity and mortality from cardiovascular disease, diabetes mellitus and certain cancers. The prevalence of obesity is increasing rapidly throughout the world and is now recognized as a major global public-health concern. Although the increased prevalence of obesity is undoubtedly driven by environmental factors, the evidence that inherited factors profoundly influence human fat mass is equally compelling. Twin and adoption studies indicate that up to 70% of the interindividual variance in fat mass is determined by genetic factors. Genetic strategies can, therefore, provide a useful tool with which to dissect the complex (and often heterogeneous) molecular and physiologic mechanisms involved in the regulation of body weight. In this Review, we have focused our attention on monogenic disorders, which primarily result in severe, early-onset obesity. The study of these genetic disorders has provided a framework for our understanding of the mechanisms involved in the regulation of body weight in humans and how these mechanisms are disrupted in obesity. The genes affected in these monogenic disorders all encode ligands and receptors of the highly conserved leptin–melanocortin pathway, which is critical for the regulation of food intake and body weight.

Key Points

  • Leptin regulates eating behavior, T-cell-mediated immunity and the onset of puberty

  • Mutations in the pro-opiomelanocortin gene (POMC) cause adrenocorticotropic hormone deficiency, severe obesity and hypopigmentation

  • Melanocortin receptor 4 (MC4R) deficiency is dominantly inherited with variable penetrance and expression

  • Mutation of the brain-derived neurotrophic factor gene (BDNF) and the tyrosine kinase receptor B gene (NTRK2) causes developmental delay, severe obesity, hyperactivity and impaired memory

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Leptin-induced signal transduction.
Figure 2: Leptin-induced signaling in the hypothalamus.
Figure 3: Structure of the pro-opiomelanocortin gene product.
Figure 4: Melanocortin receptor 4 is a seven transmembrane domain G-protein-coupled receptor.

References

  1. 1

    Barsh GS et al. (2000) Genetics of body-weight regulation. Nature 404: 644–651

    CAS  Article  Google Scholar 

  2. 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

    CAS  Article  Google Scholar 

  3. 3

    Dina C et al. (2007) Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 39: 724–726

    CAS  Article  Google Scholar 

  4. 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

    Article  Google Scholar 

  5. 5

    Gerken T et al. (2007) The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 318: 1469–1472

    CAS  Article  Google Scholar 

  6. 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

    CAS  Article  Google Scholar 

  7. 7

    Wardle J et al. (2008) Obesity-associated genetic variation in FTO is associated with diminished satiety. J Clin Endocrinol Metab [10.1210/jc.2008-0472]

  8. 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

    CAS  Article  Google Scholar 

  9. 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

    CAS  Article  Google Scholar 

  10. 10

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

    CAS  Article  Google Scholar 

  11. 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

    CAS  Article  Google Scholar 

  12. 12

    Ahima RS et al. (1996) Role of leptin in the neuroendocrine response to fasting. Nature 382: 250–252

    CAS  Article  Google Scholar 

  13. 13

    Elmquist JK et al. (1998) Distributions of leptin receptor mRNA isoforms in the rat brain. J Comp Neurol 395: 535–547

    CAS  Article  Google Scholar 

  14. 14

    Tartaglia LA (1997) The leptin receptor. J Biol Chem 272: 6093–6096

    CAS  Article  Google Scholar 

  15. 15

    Myers MG et al. (2008) Mechanisms of leptin action and leptin resistance. Annu Rev Physiol 70: 537–556

    CAS  Article  Google Scholar 

  16. 16

    Bates SH et al. (2003) STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 421: 856–859

    CAS  Article  Google Scholar 

  17. 17

    Schwartz MW et al. (2000) Central nervous system control of food intake. Nature 404: 661–671

    CAS  Article  Google Scholar 

  18. 18

    Pritchard LE et al. (2002) Pro-opiomelanocortin processing in the hypothalamus: impact on melanocortin signalling and obesity. J Endocrinol 172: 411–421

    CAS  Article  Google Scholar 

  19. 19

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

    CAS  Article  Google Scholar 

  20. 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

    CAS  Article  Google Scholar 

  21. 21

    Strobel A et al. (1998) A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 18: 213–215

    CAS  Article  Google Scholar 

  22. 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

    CAS  Article  Google Scholar 

  23. 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

    CAS  Article  Google Scholar 

  24. 24

    Farooqi IS et al. (2001) Partial leptin deficiency and human adiposity. Nature 414: 34–35

    CAS  Article  Google Scholar 

  25. 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

    CAS  Article  Google Scholar 

  26. 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

    CAS  Article  Google Scholar 

  27. 27

    Farooqi IS et al. (2007) Leptin regulates striatal regions and human eating behavior. Science 317: 1355

    CAS  Article  Google Scholar 

  28. 28

    Clément K et al. (1998) A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392: 398–401

    Article  Google Scholar 

  29. 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

    CAS  Article  Google Scholar 

  30. 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

    CAS  Article  Google Scholar 

  31. 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

    CAS  Article  Google Scholar 

  32. 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

    CAS  Article  Google Scholar 

  33. 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

    CAS  Article  Google Scholar 

  34. 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

    CAS  Article  Google Scholar 

  35. 35

    Cone RD (1999) The central melanocortin system and energy homeostasis. Trends Endocrinol Metab 10: 211–216

    CAS  Article  Google Scholar 

  36. 36

    Coll AP et al. (2004) Proopiomelanocortin and energy balance: insights from human and murine genetics. J Clin Endocrinol Metab 89: 2557–2562

    CAS  Article  Google Scholar 

  37. 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

    CAS  Article  Google Scholar 

  38. 38

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

    CAS  Article  Google Scholar 

  39. 39

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

    CAS  Article  Google Scholar 

  40. 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

    CAS  Article  Google Scholar 

  41. 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

    CAS  Article  Google Scholar 

  42. 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

    CAS  Article  Google Scholar 

  43. 43

    Farooqi IS et al. (2006) Heterozygosity for a POMC-null mutation and increased obesity risk in humans. Diabetes 55: 2549–2553

    CAS  Article  Google Scholar 

  44. 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

    CAS  Article  Google Scholar 

  45. 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

    CAS  Article  Google Scholar 

  46. 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

    Article  Google Scholar 

  47. 47

    Biebermann H et al. (2006) A role for beta-melanocyte-stimulating hormone in human body-weight regulation. Cell Metab 3: 141–146

    CAS  Article  Google Scholar 

  48. 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

    CAS  Article  Google Scholar 

  49. 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

    CAS  Article  Google Scholar 

  50. 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

    CAS  Article  Google Scholar 

  51. 51

    Pogozheva ID et al. (2005) Interactions of human melanocortin 4 receptor with nonpeptide and peptide agonists. Biochemistry 44: 11329–11341

    CAS  Article  Google Scholar 

  52. 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

    CAS  Article  Google Scholar 

  53. 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

    CAS  Article  Google Scholar 

  54. 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

    CAS  Article  Google Scholar 

  55. 55

    Stutzmann F et al. (2008) Prevalence of MC4R deficiency in European population and their age-dependant penetrance in multi-generational pedigrees. Diabetes [10.2337/db08-0153]

  56. 56

    Nogueiras R et al. (2007) The central melanocortin system directly controls peripheral lipid metabolism. J Clin Invest 117: 3475–3488

    CAS  Article  Google Scholar 

  57. 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

    CAS  Article  Google Scholar 

  58. 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

    CAS  Article  Google Scholar 

  59. 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

    CAS  Article  Google Scholar 

  60. 60

    Kernie SG et al. (2000) BDNF regulates eating behavior and locomotor activity in mice. EMBO J 19: 1290–1300

    CAS  Article  Google Scholar 

  61. 61

    Xu B et al. (2003) Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci 6: 736–742

    CAS  Article  Google Scholar 

  62. 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

    CAS  Article  Google Scholar 

  63. 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

    CAS  Article  Google Scholar 

  64. 64

    Otvos L Jr et al. (2008) Development of a pharmacologically improved peptide agonist of the leptin receptor. Biochim Biophys Acta [10.1016/j.bbamcr.2008.05.007]

  65. 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

    CAS  Article  Google Scholar 

  66. 66

    Emmerson PJ et al. (2007) Melanocortin-4 receptor agonists for the treatment of obesity. Curr Top Med Chem 7: 1121–1130

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to I Sadaf Farooqi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Farooqi, I., O'Rahilly, S. Mutations in ligands and receptors of the leptin–melanocortin pathway that lead to obesity. Nat Rev Endocrinol 4, 569–577 (2008). https://doi.org/10.1038/ncpendmet0966

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing