FTO (Fat mass and Obesity related) is the first and most robust common obesity gene yet described, with risk alleles being present in >50% of individuals in most populations. Carriers of obesity risk alleles consistently show evidence for increased appetite and food intake. Mice and humans lacking FTO however, display severe growth retardation, while overexpression of FTO in mice results in obesity. This link between FTO, growth and energy balance remains unknown.
In research recently published in PNAS, studies led by Dr Pawan Gulati and Dr Giles Yeo have shown that FTO plays a key role in the cellular sensing of amino-acids and the regulation of cell growth and global mRNA translation through the mTORC1 pathway.
How do these findings relate to the association between FTO SNPs and obesity? In humans, this association is largely driven by effects on appetite and food intake rather than energy expenditure or nutrient partitioning. The sensing of amino acid levels in the brain has critical impacts on the activity of orexigenic and anorexigenic pathways controlling energy balance and FTO is most highly expressed in the brain. Subtle effects of the risk alleles on expression of FTO in key brain centres concerned with the control of energy balance are likely to influence the way in which these cells sense amino acid levels. It is notable that human carriers of the obesity predisposing SNPs in FTO not only consume more calories at test meals but also show an alteration in nutrient preference suggesting that FTO status can influence the central sensing of dietary macronutrient composition. Thus the role of FTO in amino acid sensing may provide some clues towards understanding the cellular basis for this physiological phenomenon.
This study is published in the following article
Pawan Gulati, Man Ka Cheung, Robin Antrobus, Chris D. Church, Heather P. Harding, Yi-Chun Loraine Tung, Debra Rimmington, Marcella Ma, David Ron, Paul J. Lehner, Frances M. Ashcroft, Roger D. Cox, Anthony P. Coll, Stephen O’Rahilly, and Giles S. H. Yeo
Proc. Natl. Acad. Sci. USA Published online before print January 28, 2013, doi:10.1073/pnas.1222796110 PNAS January 28, 2013 201222796