Hypothalamic steroid receptor coactivator-2 regulates adaptations to fasting and overnutrition.

Abstract

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.

• Authors: Yongjie Yang, Yanlin He, Hailan Liu, Wenjun Zhou, Chunmei Wang, Pingwen Xu, Xing Cai, Hesong Liu, Kaifan Yu, Zhou Pei, Ilirjana Hyseni, Makoto Fukuda, Qingchun Tong, Jianming Xu, Zheng Sun, Bert W O'Malley, Yong Xu
• Journal: Cell reports (Cell Rep) Vol. 37 Issue 10 Pg. 110075 (12 07 2021) ISSN: 2211-1247 [Electronic] United States
• PMID: 34879284 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Forkhead Transcription Factors
• Foxi1 protein, mouse
• Ncoa2 protein, mouse
• Nuclear Receptor Coactivator 2
• Pro-Opiomelanocortin

Topics

• Animals
• Anxiety (metabolism, physiopathology, psychology)
• Disease Models, Animal
• Energy Metabolism
• Fasting (metabolism, psychology)
• Feeding Behavior
• Forkhead Transcription Factors (genetics, metabolism)
• HEK293 Cells
• Humans
• Hypothalamus (metabolism, physiopathology)
• Male
• Mice, Knockout
• Neurons (metabolism)
• Nuclear Receptor Coactivator 2 (genetics, metabolism)
• Obesity (genetics, metabolism, physiopathology, psychology)
• Overnutrition (genetics, metabolism, physiopathology, psychology)
• Pro-Opiomelanocortin (genetics, metabolism)
• Satiety Response
• Signal Transduction
• Weight Gain
• Mice