Succinate Prevents Mice Obesity by Enhancing Brown Adipocyte Thermogenesis via the SDH-METTL3-HIF1A Pathway

Succinate, a tricarboxylic acid (TCA) cycle intermediate, is the essential signal molecule that links metabolic signals and inflammation. Dietary succinate supplementation has been reported to prevent obesity induced by a high-fat diet (HFD). However, the underlying mechanism remains elusive. Here, we found that dietary succinate elevated the serum succinate levels. Meanwhile, we found succinate increased methyltransferaselike 3 (METTL3) protein expression in brown adipocytes, thereby elevating N6-methyladenosine (m6A) levels in Hypoxia-inducible factor1-alpha (Hif1a) mRNA. Hif1a mRNA is recognized by the m6A-binding protein YTH domain-containing family protein 1 (YTHDF1), facilitating HIF1A protein expression. HIF1A activates the transcription of thermogenic genes, ultimately increasing brown adipose energy expenditure. Together, our research provided new insights into the effect of succinate on m6A modification in brown adipose tissue thermogenesis.