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Genetics of Obesity

  • Genomics In Human Disease
  • Published:
American Journal of Pharmacogenomics

Abstract

Obesity is a typical common multifactorial disease in which environmental and genetic factors interact. In rare cases of severe obesity with childhood onset, a single gene has a major effect in determining the occurrence of obesity, with the environment having only a permissive role in the severity of the phenotype. Exceptional mutations of the leptin gene and its receptor, pro-opiomelanocortine (POMC), prohormone convertase 1 (PC1) and more frequently, mutations in the melanocortin receptor 4 (1 to 4% of very obese cases) have been described. All these obesity genes encode proteins that are strongly connected as part of the same loop of the regulation of food intake. They all involve the leptin axis and one of its hypothalamic targets; the melanocortin pathway.

Pathways of body weight regulation involved in monogenic forms of obesity might represent targets for future drug development. Successful leptin protein replacement in a leptin-deficient child has contributed to the validation of the usefulness of gene screening in humans. However, the individual variability in response to leptin treatment might be related to genetic variability. The efficiency of leptin itself or of small-molecule agonists of the leptin receptor should be studied in relation with genetic variations in the leptin gene promoter.

The most common forms of obesity are polygenic. Two general approaches have been used to date in the search for genes underlying common polygenic obesity in humans. The first approach focuses on selected genes having some plausible role in obesity on the basis of their known or presumed biological role. This approach yielded putative susceptibility genes with only small or uncertain effects. The second approach attempts to map genes purely by position and requires no presumptions on the function of genes. Genome-wide scans identify chromosomal regions showing linkage with obesity in large collections of nuclear families. Genome-wide scans in different ethnic populations have localized major obesity loci on chromosomes 2, 5, 10, 11 and 20. Susceptibility gene(s) for obesity may be positionally cloned in the intervals of linkage. The candidate gene and positional cloning of major obesity-linked regions approaches are discussed in this paper.

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Acknowledgements

This work was supported by the CNRS, a grant from Eli Lilly, the direction de la Recherche Clinique/Assistance Publique-Hopitaux de Paris, Programme Hospitalier de Recherche Clinique (PHRC AOM 96088, P921015) and by the Institut de Recherche Internationale Servier.

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  1. CNRS-Institute of Biology of Lille, Institut Pasteur de Lille, 1 rue Calmette, BP245, Lille, 59016, France

    Karine Clement, Philippe Boutin &  Philippe Froguel

  2. Laboratory and Department of Nutrition, Hotel Dieu, Paris, France

    Karine Clement

  3. Saint Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, University of London, London, UK

    Philippe Froguel

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Correspondence to Philippe Froguel.

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Clement, K., Boutin, P. & Froguel, P. Genetics of Obesity. Am J Pharmacogenomics 2, 177–187 (2002). https://doi.org/10.2165/00129785-200202030-00003

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