OBJECTIVE 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. METHODS 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. RESULTS 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. CONCLUSIONS Together, our results indicate that the microbial metabolite butyrate regulates thermogenesis in BAT and scWAT through the activation of LSD1.

中文翻译：

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LSD1介导棕色和白色脂肪组织中微生物代谢物丁酸酯诱导的生热作用。

目的肠道菌群至少部分地通过其代谢产物丁酸盐调节生热，从而有利于代谢稳态，而这种调节的潜在机制仍不清楚。在这项研究中，我们旨在研究赖氨酸特异性脱甲基酶（LSD1），组蛋白脱甲基酶和生热的重要调节剂在介导肠道微生物代谢产物丁酸对生热的调节中的作用。方法服用抗生素鸡尾酒（ABX）消耗肠道菌群。通过将LSD1-lox / lox与脂联素-cre小鼠杂交，产生脂肪特异性LSD1基因敲除小鼠（LSD1 aKO），并通过管饲法施用丁酸钠和膳食纤维菊粉。从脂肪组织中分离出原代基质血管细胞，并分化为脂肪细胞，以研究丁酸酯对脂肪细胞生热的影响。结果抗生素鸡尾酒（ABX）介导的小鼠肠道菌群耗竭除了调节蛋白1（UCP1）和体温外，还降低了棕色脂肪组织（BAT）和皮下白色脂肪组织（scWAT）中LSD1的表达。管饲ABX处理的小鼠中的微生物代谢产物丁酸酯逆转了热原性功能障碍和LSD1表达。LSD1在小鼠中的脂肪特异性消融减弱了丁酸酯介导的生热作用和能量消耗。尤其，我们的结果表明，丁酸直接增加了离体培养的脂肪细胞中LSD1和UCP1以及丁酸转运蛋白单羧酸盐转运蛋白1（MCT1）和分解代谢酶酰基辅酶A中链合成酶3（ACSM3）的表达。MCT1的抑制作用阻止了脂肪细胞中丁酸酯的作用。此外，在LSD1 aKO小鼠中，丁酸介导的通过增加生热作用来预防饮食诱发的肥胖（DIO）的作用减弱。此外，在饲喂高脂饮食的小鼠中添加膳食纤维菊粉后，微生物发酵的底物迅速产生丁酸酯，BAT和scWAT的生热增加，DIO降低；但是，这些有益的代谢作用在LSD1 aKO小鼠中被阻断。结论在一起，