Dietary timing enhances exercise by modulating fat-muscle crosstalk via adipocyte AMPKα2 signaling

Jianghui Chen; Jing Xiang; Meiyu Zhou; Rongfeng Huang; Jianxin Zhang; Yuanting Cui; Xiaoqing Jiang; Yang Li; Runchao Zhou; Haoran Xin; Jie Li; Lihua Li; Sin Man Lam; Jianfang Zhu; Yanxiu Chen; Qingyuan Yang; Zhifu Xie; Guanghou Shui; Fang Deng; Zhihui Zhang; Min-Dian Li

doi:10.1016/j.cmet.2025.02.007

Dietary timing enhances exercise by modulating fat-muscle crosstalk via adipocyte AMPKα2 signaling

Cell Metab. 2025 Mar 12:S1550-4131(25)00065-8. doi: 10.1016/j.cmet.2025.02.007. Online ahead of print.

Authors

Jianghui Chen¹, Jing Xiang¹, Meiyu Zhou¹, Rongfeng Huang², Jianxin Zhang³, Yuanting Cui¹, Xiaoqing Jiang¹, Yang Li¹, Runchao Zhou¹, Haoran Xin¹, Jie Li¹, Lihua Li¹, Sin Man Lam⁴, Jianfang Zhu¹, Yanxiu Chen¹, Qingyuan Yang¹, Zhifu Xie⁵, Guanghou Shui⁶, Fang Deng⁷, Zhihui Zhang⁸, Min-Dian Li⁹

Affiliations

¹ Department of Cardiovascular Medicine, Center for Circadian Metabolism and Cardiovascular Disease, Southwest Hospital, Army Medical University, Chongqing 400038, China; Ministry of Education Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease, Chongqing 400038, China.
² Department of Cardiovascular Medicine, Center for Circadian Metabolism and Cardiovascular Disease, Southwest Hospital, Army Medical University, Chongqing 400038, China; Ministry of Education Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease, Chongqing 400038, China; Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610072, China.
³ Department of Cardiovascular Medicine, Center for Circadian Metabolism and Cardiovascular Disease, Southwest Hospital, Army Medical University, Chongqing 400038, China; Ministry of Education Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease, Chongqing 400038, China; Department of Cardiology, The 960th Hospital of the PLA Joint Service Support Force, Jinan 250000, China.
⁴ State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; LipidALL Technologies Company Limited, Changzhou, China.
⁵ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁶ State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
⁷ Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing 400038, China; Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing 400038, China; Key Laboratory of High Altitude Medicine, PLA, Chongqing 400038, China.
⁸ Department of Cardiovascular Medicine, Center for Circadian Metabolism and Cardiovascular Disease, Southwest Hospital, Army Medical University, Chongqing 400038, China; Ministry of Education Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease, Chongqing 400038, China. Electronic address: xyzpj@tmmu.edu.cn.
⁹ Department of Cardiovascular Medicine, Center for Circadian Metabolism and Cardiovascular Disease, Southwest Hospital, Army Medical University, Chongqing 400038, China; Ministry of Education Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease, Chongqing 400038, China. Electronic address: mindianli@tmmu.edu.cn.

PMID: 40088888
DOI: 10.1016/j.cmet.2025.02.007

Abstract

Feeding rhythms regulate exercise performance and muscle energy metabolism. However, the mechanisms regulating adipocyte functions remain unclear. Here, using multi-omics analyses, involving (phospho-)proteomics and lipidomics, we found that day-restricted feeding (DRF) regulates diurnal rhythms of the mitochondrial proteome, neutral lipidome, and nutrient-sensing pathways in mouse gonadal white adipose tissue (GWAT). Adipocyte-specific knockdown of Prkaa2 (the gene encoding AMPKα2) impairs physical endurance. This defect is associated with altered rhythmicity in acyl-coenzyme A (CoA) metabolism-related genes, a loss of rhythmicity in the GWAT lipidome, and circadian remodeling of serum metabolites-in particular, lactate and succinate. We also found that adipocyte Prkaa2 regulates muscle clock genes during DRF. Notably, oral administration of the AMPK activator C29 increases endurance and muscle functions in a time-of-day manner, which requires intact adipocyte AMPKα2 signaling. Collectively, our work defines adipocyte AMPKα2 signaling as a critical regulator of circadian metabolic coordination between fat and muscle, thereby enhancing exercise performance.

Keywords: AMPK; adipocyte; adipose tissue; chrono-medicine; circadian clock; circadian rhythm; day-restricted feeding; exercise physiology; feeding rhythm; multi-omics.