The rs1421085 variant within FTO promotes thermogenesis and is associated with human migration

Abstract One lead risk signal of obesity–rs1421085 T > C within the FTO gene–is reported to be functional in vitro but lack of organismal evidence. Here, we established global and the brown-adipocyte specific locus-knock-in mice to recapitulate this homologous variant in humans and discovered that mice carrying the C-alleles showed increased thermogenic capacity and a resistance to high-fat diet-induced adiposity with enhanced FTO transcription, while FTO knockdown or inhibition effectively eliminated the increased thermogenic ability of brown adipocytes. In humans, the C-allele was associated with lower birthweight, and its allele frequency increases following the environmental temperature decreases. Cumulatively, these findings identified rs1421085 T > C as a functional variant promoting whole-body thermogenesis and was associated with early human migration from hot to cold environments.