In 2007 a genome wide association study linked SNPs in intron 1 of FTO with an increased body mass index. Individuals with the risk allele are on average 3 kg heavier than those with the protective allele. Furthermore, those with the risk allele have demonstrated greater energy intake. Mouse models of FTO have been generated including a conditional overexpression allele of FTO, which has 2 additional copies of FTO (FTO-4). These mice have increased body weight when globally expressed, which suggests that the FTO SNPs may lead to weight gain by increasing the activity and/or expression levels of FTO.
FTO-4 mice are hyperphagic. To investigate the cause, hormones, which are crucial for control of food intake and satiety, will be analysed.
Male 6 weeks old FTO-4 and wild-type mice fed on high fat diet were acclimatised to 16 h overnight fasting for 3 weeks. In subsequent weeks after fasting blood samples, food intake and body weight, fat and lean mass data and finally tissues were collected. Analysis of blood and tissue samples was then performed.
Significant dysregulation of specific hormones can be seen. Active ghrelin levels were either significantly higher in FTO-4 mice following refeeding or significantly lower before feeding began. Levels of leptin were significantly higher in FTO-4 mice (P=0.006) than in wild-types following refeeding suggesting resistance to leptins anorexigenic effects. Levels of NPY, an orexigenic neuropeptide, were also significantly higher (P=0.0003) in FTO-4 mice following refeeding.
This dysregulation may contribute to the hyperphagia seen in the FTO-4 mice. Weekly fasting prevented the increased body weight phenotype, and any early significant differences were reversed. Therefore limiting excess access to food through paired-feeding experiments may prevent obesity in FTO-4 mice. These further experiments should help to establish how the FTO risk allele can affect obesity in humans.
30 Apr - 04 May 2011
European Society of Endocrinology