Editors' ChoiceHuman Genetics

Decoding Obesity

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Science Translational Medicine  15 Dec 2010:
Vol. 2, Issue 62, pp. 62ec194
DOI: 10.1126/scitranslmed.3002014

By 2030, over 1 billion adults in the world will be overweight or obese. The corresponding increases in obesity-related diseases, including diabetes, heart disease, and cancer, are equally staggering. Thus, stemming the tide of obesity is of key importance for global health, although how to tackle this problem remains unclear. Recent genetic studies may help by elucidating new molecular pathways that contribute to obesity. In particular, single-nucleotide polymorphisms (SNPs) in the FTO gene—which encodes a nucleic acid demethylase—have been strongly linked to obesity in several genome-wide association studies. Moreover, over 15% of Europeans are homozygous for the at-risk allele and are on average seven pounds heavier than noncarriers.

Now, Church et al. demonstrate exactly how FTO variants might be contributing to obesity. In a multistage experiment, they created mice carrying one or two extra copies of the ubiquitously expressed Fto gene. Subsequently, they found that mice with one or two extra copies of Fto, when fed a standard diet, had a 42 or 85% increase in fat mass, respectively, when compared with that of control mice. The Fto mutants also exhibited an increased propensity for food intake and impaired glucose tolerance as compared with those of their wild-type littermates—which is a hallmark of type 2 diabetes. Notably, lower levels of circulating leptin were also observed in mice overexpressing Fto. This is of particular significance, given that leptin deficiency has been linked to hyperphagia. Taken together, these exciting findings indicate that FTO could be a valuable therapeutic target for the development of new anti-obesity drugs. However, several questions must first be resolved. Foremost, do the effects of human-susceptibility SNPs result in overexpression of FTO? Second, are the effects of FTO variants mediated through the central nervous system, controlling food intake, or are the effects conferred through peripheral tissues mediating energy expenditure? Irrespective of the biological link between FTO variants and obesity, further understanding of the FTO gene and the nucleic acid demethylase it encodes will be essential for decoding the mechanisms that lead to obesity in humans.

C. Church et al., Overexpression of Fto leads to increased food intake and results in obesity. Nat. Genet. 42, 1086–1092 (2010). [Abstract]

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