Eleanor Bagg - A mouse model for the metabolic effects of the human fat mass and obesity associated FTO gene

Version 1

      Publication Details (including relevant citation   information):

      PLoS Genet. 2009 (8):e1000599

      Abstract:

      Human FTO gene variants are associated with body mass index and   type 2  diabetes. Because the obesity-associated SNPs are   intronic, it is  unclear whether changes in FTO expression   or splicing are the cause of  obesity or if regulatory   elements within intron 1 influence upstream or  downstream   genes. We tested the idea that FTO itself is involved in    obesity. We show that a dominant point mutation in the mouse Fto   gene  results in reduced fat mass, increased energy   expenditure, and unchanged  physical activity. Exposure to a   high-fat diet enhances lean mass and  lowers fat mass   relative to control mice. Biochemical studies suggest  the   mutation occurs in a structurally novel domain and modifies   FTO  function, possibly by altering its dimerisation state.   Gene expression  profiling revealed increased expression of   some fat and carbohydrate  metabolism genes and an improved   inflammatory profile in white adipose  tissue of mutant   mice. These data provide direct functional evidence  that   FTO is a causal gene underlying obesity. Compared to the   reported  mouse FTO knockout, our model more accurately   reflects the effect of  human FTO variants; we observe a   heterozygous as well as homozygous  phenotype, a smaller   difference in weight and adiposity, and our mice do  not   show perinatal lethality or an age-related reduction in size   and  length. Our model suggests that a search for human   coding mutations in  FTO may be informative and that   inhibition of FTO activity is a possible  target for the   treatment of morbid obesity.

      Address (URL): http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000599