Endocrine Abstracts (2010) 21 S6.1

FTO variants are associated with overeating and many long-term health problems associated with obesity

C Palmer

University of Dundee, Dundee, UK.

Monogenic obesity disorders and mouse models of obesity have overwhelmingly pointed to hyperphagia as the predominant genetic force in promoting obesity, it was therefore no surprise when the most robust common variant associated with obesity from GWAS studies was associated with increased energy intake. We and other groups have shown that variants in the FTO gene are not associated with increased food intake per se, but rather display a preference for energy dense foods resulting in an increased calorific intake. This leads to an increase in BMI that is readily detectable in children as young as four years of age. This increase in BMI is largely due to an increase in whole body fat mass, and specific fat depots are not selectively involved in this phenotype. Mice deleted for the FTO locus display hyperphagia, however increased metabolism leads to a leaner phenotype, whereas in the humans increased metabolism is also observed in the hyperphagic minor allele carriers, but this is clearly not sufficient to prevent obesity in these individuals. This increased BMI from early childhood to adulthood leads to an increased risk of type 2 diabetes, dyslipidemia, hypertension and finally results in premature death through cardiovascular disease. These observations represent a clear mendelian randomisation experiment confirming the powerful causal role of poor dietary habits and obesity in driving premature morbidity and mortality being observed in many populations around the world.

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