Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Cell Rep. 2021 Dec 7;37(10):110075. doi: 10.1016/j.celrep.2021.110075.
The neuroendocrine system coordinates metabolic and behavioral adaptations to fasting, including reducing energy expenditure, promoting counterregulation, and suppressing satiation and anxiety to engage refeeding. Here, we show that steroid receptor coactivator-2 (SRC-2) in pro-opiomelanocortin (POMC) neurons is a key regulator of all these responses to fasting. POMC-specific deletion of SRC-2 enhances the basal excitability of POMC neurons; mutant mice fail to efficiently suppress energy expenditure during food deprivation. SRC-2 deficiency blunts electric responses of POMC neurons to glucose fluctuations, causing impaired counterregulation. When food becomes available, these mutant mice show insufficient refeeding associated with enhanced satiation and discoordination of anxiety and food-seeking behavior. SRC-2 coactivates Forkhead box protein O1 (FoxO1) to suppress POMC gene expression. POMC-specific deletion of SRC-2 protects mice from weight gain induced by an obesogenic diet feeding and/or FoxO1 overexpression. Collectively, we identify SRC-2 as a key molecule that coordinates multifaceted adaptive responses to food shortage.
神经内分泌系统协调代谢和行为适应禁食，包括降低能量消耗、促进代偿、抑制饱腹感和焦虑以进行再进食。在这里，我们表明，促阿黑皮素原（POMC）神经元中的类固醇受体共激活因子-2（SRC-2）是对所有这些禁食反应的关键调节因子。POMC 特异性敲除 SRC-2 增强了 POMC 神经元的基础兴奋性；突变小鼠在禁食期间无法有效地抑制能量消耗。SRC-2 缺乏会削弱 POMC 神经元对葡萄糖波动的电反应，导致代偿功能受损。当食物变得可用时，这些突变小鼠表现出与饱腹感增强和焦虑与觅食行为不协调相关的不足再进食。SRC-2 共激活叉头框蛋白 O1（FoxO1）以抑制 POMC 基因表达。POMC 特异性敲除 SRC-2 可保护小鼠免受肥胖饮食喂养和/或 FoxO1 过表达引起的体重增加。总的来说，我们确定 SRC-2 是协调对食物短缺的多方面适应性反应的关键分子。
