m6A methylation promotes white-to-beige fat transition by facilitating Hif1a translation

Obesity mainly results from a chronic energy imbalance. Promoting browning of white adipocytes is a promising strategy to enhance energy expenditure and combat obesity. N6-methyladenosine (m6A), the most abundant mRNA modification in eukaryotes, plays an important role in regulating adipogenesis. However, whether m6A regulates white adipocyte browning was unknown. Here, we report that adipose tissue-specific deletion of Fto, an m6A demethylase, predisposes mice to prevent high-fat diet (HFD)-induced obesity by enhancing energy expenditure. Additionally, deletion of FTO in vitro promotes thermogenesis and white-to-beige adipocyte transition. Mechanistically, FTO deficiency increases the m6A level of Hif1a mRNA, which is recognized by m6A-binding protein YTHDC2, facilitating mRNA translation and increasing HIF1A protein abundance. HIF1A activates the transcription of thermogenic genes, including Ppaggc1a, Prdm16, and Pparg, thereby promoting Ucp1 expression and the browning process. Collectively, these results unveil an epigenetic mechanism by which m6A-facilitated HIF1A expression controls browning of white adipocytes and thermogenesis, providing a potential target to counteract obesity and metabolic disease. Synopsis FTO loss in adipose tissue protects against HFD-induced obesity via promoting energy expenditure. FTO loss increases HIF1A m6A levels and protein abundance. HIF1A activates thermogenic gene transcription thereby promoting the browning process. Adipose tissue-specific deletion of Fto predisposes mice to prevent high-fat diet (HFD)-induced obesity by enhancing energy expenditure. FTO deficiency in adipose tissue increases the levels of Hif1a m6A, which is recognized and bound by m6A-binding protein YTHDC2, facilitating Hif1a mRNA translation and HIF1A protein abundance. HIF1A activates the transcription of thermogenic genes, which promotes the browning process and counteracts obesity. Graphical Abstract FTO loss in adipose tissue protects against HFD-induced obesity via promoting energy expenditure. FTO loss increases HIF1A m6A levels and protein abundance. HIF1A activates thermogenic gene transcription thereby promoting the browning process.