Article
作者: Lyu, Qianqian ; Yan, Fuhua ; Tan, Jialin ; Bo, Tingting ; Yuan, Miaomiao ; Ning, Guang ; Zhang, Xuejiao ; Hong, Jie ; Wang, Weiqing ; Wang, Shushu ; Zhou, Feiye ; Zheng, Jie ; Wang, Xiao ; Liu, Yunxia ; Zhou, Libin ; Ma, Xiaoqin ; Xue, Wenzhi ; Sun, Haipeng ; Wang, Jiqiu ; Ming, Xing
The role of hypothalamic branched-chain amino acid (BCAA) catabolism in the maintenance of energy homeostasis remains elusive. By using Mendelian randomization, we found that genetically predicted branched-chain keto acid dehydrogenase E1α subunit (BCKDHA) expression in the hypothalamus was negatively associated with fat mass. Hypothalamic deletion of BCKDHA (Bckdhaf/f;RIP-Cre) leads to increased fat mass, reduced energy expenditure, and blunted browning of white adipose tissue in mice, with decreases of thyrotropin-releasing hormone (TRH) expression in the paraventricular nucleus (PVN) and hypothalamic-pituitary-thyroid (HPT) axis activity. Mice with adeno-associated virus-mediated deletion of BCKDHA in the PVNTRH neurons displays a similar metabolic phenotype to Bckdhaf/f;RIP-Cre mice. TRH supplementation ameliorates the abnormal phenotypes of Bckdhaf/f;RIP-Cre mice. Defective BCAA catabolism in the hypothalamus results in hypoacetylation of histone H3 lysine 27 (H3K27) due to decreased acetyl-CoA content, reducing its binding to the Trh promoter. Our study highlights the crucial role of hypothalamic BCAA catabolism in maintaining energy homeostasis through HPT axis.