Editors' ChoiceObesity

Linking an Obesity-Associated Gene Variant, Ghrelin, and the Brain

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Science Translational Medicine  31 Jul 2013:
Vol. 5, Issue 196, pp. 196ec124
DOI: 10.1126/scitranslmed.3007044

One in six people of European descent are homozygotes for the obesity-risk A allele of the FTO gene (fat-mass and obesity-associated gene). This obesity-associated variant increases a person’s risk of obesity by nearly 70%. Because the genome-wide association studies (GWASs) unearthed the FTO obesity-risk allele in 2007, scientists have worked to elucidate the mechanisms by which this variant predisposes individuals to weight gain and obesity. The hope is that a mechanistic understanding will lead to identification of new therapeutic targets for the prevention and treatment of obesity.

In a recent study, Karra et al. investigated whether a relationship exists between the obesity-risk FTO gene variant, ghrelin (the hunger hormone), and neural responses to visual food cues. From a cohort of 359 healthy, lean [mean body-mass index (BMI) of 22.5 kg/m2], young (mean age 22.9) European men, the authors matched 10 men who were homozygotes for the obesity-risk A allele (genotype AA) and 10 who were homozygotes for the low obesity-risk T allele (genotype TT) on the basis of age, BMI, fat mass, and visceral fat area. Compared to their TT counterparts, the AA men were found to have attenuated decreases in both postprandial hunger and ghrelin levels in response to eating a standard meal. Next, using functional MRI the authors examined neural activation of 12 AA men and 12 TT men in response to viewing pictures of high-calorie foods, low-calorie foods, and nonfoods. When viewing food versus nonfood pictures, AA individuals exhibited decreased neural responses (compared with those of TT individuals) in the hypothalamus, an area of the brain involved in energy homeostasis and satiety, and striatal-limbic regions involved in various functions including reward-motivation. In addition, correlations between ghrelin levels and neural response in the hypothalamus and the nucleus accumbens (a key neural reward region) were positive in TT men and negative in AA men, thus suggesting that the obesity-risk FTO gene variant affects the brain’s response to ghrelin.

This study provides a possible neurobiological mechanism by which the obesity-associated FTO gene variant may predispose individuals to weight gain: by attenuating postprandial decreases in subjective hunger and ghrelin levels and by altering neural responsivity to visual food cues in areas of the brain implicated in satiety and reward-motivation. Indeed, this interdisciplinary study lends credence to further development of potential therapeutic agents, such as ghrelin receptor antagonists, as well as continued investigation of possible new molecular targets for the prevention and treatment of obesity.

E. Karra et al., A link between FTO, ghrelin, and impaired brain food-cue responsivity. J. Clin. Invest., published online 15 July 2013 (10.1172/JCI44403). [Full Text]

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