The rs1421085 variant within FTO promotes but not inhibits thermogenesis and is potentially associated with human migration

Author:

Zhang Zhiyin,Chen Na,Liu Ruixin,Yin Nan,He Yang,Li Danjie,Tong Muye,Gao Aibo,Lu Peng,Li Huabing,Zhang Dan,Gu Weiqiong,Hong Jie,Wang Weiqing,Qi Lu,Wang Jiqiu,Ning Guang

Abstract

SummaryDisease-associated GWAS loci are predominantly scattered among noncoding regions of the human genome, which impedes causality estimation. One lead risk signal of obesity–rs1421085 T>C within the FTO gene–is reported to 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 the minor allele (C-allele) as one candidate thermogenic locus. Mice carrying the C-alleles showed increased thermogenic capacity and a resistance to high-fat diet-induced adiposity. In terms of mechanism, the knock-in models showed enhanced FTO expression, 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 demonstrated rs1421085 T>C as a functional variant regulating whole-body thermogenesis, and this variation was possibly related to early human migration from hot to cold environments.

Publisher

Cold Spring Harbor Laboratory

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