KMT5C调节棕色和米色脂肪细胞产热功能的机制研究

棕色脂肪组织和米色脂肪细胞在机体适应性产热过程中，消耗葡萄糖和脂肪而利于维持体内糖脂代谢稳态，解析脂肪细胞内适应性产热调控机制将为治疗肥胖和糖尿病提供新的药物靶点。组蛋白甲基化修饰影响染色体结构或非组蛋白与染色体结合，从而参与调节各种生命活动过程。组蛋白H3K4、H3K9、H3K27、H3K36位点甲基化修饰都可调控产热脂肪功能，然而H4K20甲基化修饰对脂肪细胞适应性产热过程的影响还未见报道。本研究发现H4K20甲基转移酶Kmt5c在脂肪组织中的表达明显受冷暴露或β3肾上腺素受体激动剂诱导，在棕色或米色脂肪细胞中敲低Kmt5c表达，则导致Ucp1、Cidea等产热相关基因表达显著下降，提示Kmt5c参与调节脂肪细胞产热功能。本项目拟构建脂肪组织敲除Kmt5c小鼠模型，系统研究体内Kmt5c敲除对脂肪细胞功能影响及其发挥作用机制，为靶向Kmt5c治疗肥胖等代谢性疾病奠定实验基础。

Brown adipose tissue (BAT) and beige adipocytes dissipate energy by producing heat to maintain body temperature in a process called adaptive thermogenesis. The beneficial effects of burning glucose and fatty acids during thermogenesis have raised intense interest in understanding the regulation of this process. Elucidating the regulatory mechanisms underlying the thermogenic adipose program may provide excellent targets for therapeutics against obesity and diabetes. Histone methylation dictates chromatin structure or affects the recruitment of non-histone proteins to chromatin, influencing many fundamental biological processes. Methylation on Histone H3K4, H3K9, H3K27 and H3K36 was reported to modulate brown and beige adipocytes functions, but little is known about the effects of Histone H4K20 methylation on thermogenic adipose program. Here we find the expression of Kmt5c, a H4K20 methyltransferase, is dramatically induced by cold exposure or β3-adrenergic signaling in adipose tissues. Kmt5c is required for Ucp1 and Cidea expression in both brown and beige adipocytes but not for adipogenesis per se, as indicated by the fact that knockdown of Kmt5c significantly downregulates expression of Ucp1 and Cidea. Next, we are going to set up adipose tissue-specific Kmt5c knockout mice, reveal the roles of Kmt5c playing in vivo and elucidate the underlying mechanisms. It may illuminate a new therapeutic strategy for the treatment of obesity and the related diseases.