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

Nature Clinical Practice Endocrinology & Metabolism volume 4, pages 569–577 (2008)Cite this article

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

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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.

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Authors and Affiliations

  1. IS Farooqi is a Wellcome Senior Clinical Fellow and S O'Rahilly is a Professor of Clinical Biochemistry in the University of Cambridge Metabolic Research Laboratories at Addenbrooke's Hospital, Cambridge, UK.,

    I Sadaf Farooqi & Stephen O'Rahilly

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Correspondence to I Sadaf Farooqi.

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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

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