肠道菌群广泛参与宿主整体代谢的调节，包括丁酸在内的肠道菌群代谢物在机体能量代谢中的作用日益受到关注。本课题组前期研究结果显示丁酸钠能显著增加多个胰岛β细胞功能相关基因的表达及胰岛素分泌，上调胰岛组蛋白乙酰化水平。蛋白质谱结果显示组蛋白去乙酰化酶1（HDAC1）存在β-羟基丁酰化修饰，该修饰的底物β-羟基丁酰辅酶A可在丁酸代谢过程中产生，而羟酰基辅酶A脱氢酶（HADH）表达降低进一步增加丁酸钠的胰岛素促泌作用。本课题拟采用HADH敲除小鼠、腺病毒转染、Seahorse细胞能量代谢检测、免疫共沉淀和ChIP-sequence等技术，观察丁酸钠是否通过其中间代谢产物酰化修饰并抑制HDAC1活性，增加组蛋白乙酰化水平，增强β细胞功能，探索丁酸作为肠道信使分子调控机体能量代谢新的作用模式，为2型糖尿病的药物研发提供新的策略。

A growing body of evidence reveals that gut microbiota plays an important role in the regulation of host metabolism. The role of gut microbial metabolite including butyrate in energy metabolism is becoming more and more concerned. Our previous data showed that sodium butyrate (SB) increased the expression of multiple genes involved in the regulation of pancreatic β-cell function and insulin secretion from isolated rat islets and up-regulated histone acetylation levels. The results of tandem mass spectrometry revealed that histone deacetylase 1 (HDAC1) was β-hydroxybutyrylated at several lysine sites. β-hydroxybutyryl-CoA is a metabolite of butyrate, and the down-regulation of hydroxy-CoA dehydrogenase (HADH) potentiated SB-induced insulin secretion. In this study we will use HADH knockout mice, adenovirus transfection, Seahorse XF extracellular flux analyzers, Co-immunoprecipitation, and ChIP-sequence techniques to detect whether butyrate β-hydroxybutyrylates and inhibits HDAC1 activity through its metabolites and promotes histone acetylation, resulting in enhanced β-cell function. This study will explore a new mechanism underlying butyrate-regulated energy metabolism as an intestinal signal and provide a new strategy for the treatment of type 2 diabetes.