LSD1 mediates microbial metabolite butyrate-induced thermogenesis in brown and white adipose tissue

The gut microbiota regulates thermogenesis to benefit metabolic homeostasis at least partially via its metabolite butyrate, and the underlying mechanisms of this regulation are still unclear. In this study, we aim to investigate the role of lysine specific demethylase (LSD1), a histone demethylase and important regulator of thermogenesis, in mediating gut microbial metabolite butyrate regulation of thermogenesis.The antibiotic cocktail (ABX) was administrated to deplete gut microbiota. Adipose-specific LSD1 knockout mice (LSD1 aKO) were generated by crossing LSD1-lox/lox with adiponectin-cre mice and sodium butyrate and dietary fiber inulin was administrated through oral-gavage. Primary stromal vascular cells were isolated from adipose tissues and differentiated to adipocytes for studying butyrate effects on adipocyte thermogenesis.The antibiotic cocktail (ABX)-mediated depletion of the gut microbiota in mice downregulated the expression of LSD1 in both brown adipose tissue (BAT) and subcutaneous white adipose tissue (scWAT) in addition to uncoupling protein 1 (UCP1) and body temperature. Gavage of the microbial metabolite butyrate in ABX-treated mice reversed the thermogenic functional impairment and LSD1 expression. The adipose-specific ablation of LSD1 in mice attenuated the butyrate-mediated induction of thermogenesis and energy expenditure. Notably, our results showed that butyrate directly increased the expression of LSD1 and UCP1 as well as butyrate transporter monocarboxylate transporter 1 (MCT1) and catabolic enzyme acyl-CoA medium-chain synthetase 3 (ACSM3) in ex vivo cultured adipocytes. The inhibition of MCT1 blocked the effects of butyrate in adipocytes. Furthermore, the butyrate-mediated prevention of diet-induced obesity (DIO) through increased thermogenesis was attenuated in LSD1 aKO mice. Moreover, after gavaging HFD-fed mice with the dietary fiber inulin, a substrate of microbial fermentation that rapidly produces butyrate, thermogenesis in both BAT and scWAT was increased, and DIO was decreased; however, these beneficial metabolic effects were blocked in LSD1 aKO mice.Together, our results indicate that the microbial metabolite butyrate regulates thermogenesis in BAT and scWAT through the activation of LSD1.