BCAA catabolism in TRH neurons of paraventricular nucleus regulates energy expenditure

IF 16.7 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental Pub Date : 2026-02-01 Epub Date: 2025-11-10 DOI:10.1016/j.metabol.2025.156435

Xing Ming , Jialin Tan , Miaomiao Yuan , Xiaoqin Ma , Feiye Zhou , Shushu Wang , Qianqian Lyu , Wenzhi Xue , Tingting Bo , Yunxia Liu , Xuejiao Zhang , Fuhua Yan , Jie Hong , Jie Zheng , Guang Ning , Weiqing Wang , Jiqiu Wang , Haipeng Sun , Libin Zhou , Xiao Wang

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Abstract

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 (Bckdha^f/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 PVN^TRH neurons displays a similar metabolic phenotype to Bckdha^f/f;RIP-Cre mice. TRH supplementation ameliorates the abnormal phenotypes of Bckdha^f/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.

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室旁核TRH神经元的支链氨基酸分解代谢调节能量消耗。

下丘脑支链氨基酸（BCAA）分解代谢在维持能量稳态中的作用尚不清楚。通过孟德尔随机化，我们发现下丘脑中可预测的支链酮酸脱氢酶E1α亚基（BCKDHA）表达与脂肪量呈负相关。下丘脑缺失BCKDHA （bckhaf /f; ripcre）导致小鼠脂肪量增加，能量消耗减少，白色脂肪组织褐变变，室旁核（PVN）促甲状腺素释放激素（TRH）表达降低，下丘脑-垂体-甲状腺（HPT）轴活性降低。腺相关病毒介导PVNTRH神经元中BCKDHA缺失的小鼠表现出与BCKDHA /f相似的代谢表型；RIP-Cre老鼠。补充TRH可改善backhaff /f的异常表型；RIP-Cre老鼠。下丘脑BCAA分解代谢缺陷导致组蛋白H3赖氨酸27 （H3K27）因乙酰辅酶a含量降低而低乙酰化，减少其与Trh启动子的结合。我们的研究强调了下丘脑BCAA分解代谢在通过HPT轴维持能量稳态中的关键作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Metabolism: clinical and experimental 医学-内分泌学与代谢

CiteScore

18.90

自引率

3.10%

发文量

310

审稿时长

16 days

期刊介绍： Metabolism upholds research excellence by disseminating high-quality original research, reviews, editorials, and commentaries covering all facets of human metabolism. Consideration for publication in Metabolism extends to studies in humans, animal, and cellular models, with a particular emphasis on work demonstrating strong translational potential. The journal addresses a range of topics, including: - Energy Expenditure and Obesity - Metabolic Syndrome, Prediabetes, and Diabetes - Nutrition, Exercise, and the Environment - Genetics and Genomics, Proteomics, and Metabolomics - Carbohydrate, Lipid, and Protein Metabolism - Endocrinology and Hypertension - Mineral and Bone Metabolism - Cardiovascular Diseases and Malignancies - Inflammation in metabolism and immunometabolism