The rs1421085 variant within FTO promotes brown fat thermogenesis

One lead genetic risk signal of obesity—the rs1421085 T>C variant within the FTO gene—is reported to be functional in vitro but lacks evidence at an organism level. Here we recapitulate the homologous human variant in mice with global and brown adipocyte-specific variant knock-in and reveal that mice carrying the C-allele show increased brown fat thermogenic capacity and resistance to high-fat diet-induced adiposity, whereas the obesity-related phenotypic changes are blunted at thermoneutrality. Both in vivo and in vitro data reveal that the C-allele in brown adipocytes enhances the transcription of the Fto gene, which is associated with stronger chromatin looping linking the enhancer region and Fto promoter. Moreover, FTO knockdown or inhibition effectively eliminates the increased thermogenic ability of brown adipocytes carrying the C-allele. Taken together, these findings identify rs1421085 T>C as a functional variant promoting brown fat thermogenesis.