2. Academic Validation
  3. Dietary timing enhances exercise by modulating fat-muscle crosstalk via adipocyte AMPKα2 signaling

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.
Jianghui Chen 1,  Jing Xiang 1,  Meiyu Zhou 1,  Rongfeng Huang 2,  Jianxin Zhang 3,  Yuanting Cui 1,  Xiaoqing Jiang 1,  Yang Li 1,  Runchao Zhou 1,  Haoran Xin 1,  Jie Li 1,  Lihua Li 1,  Sin Man Lam 4,  Jianfang Zhu 1,  Yanxiu Chen 1,  Qingyuan Yang 1,  Zhifu Xie 5,  Guanghou Shui 6,  Fang Deng 7,  Zhihui Zhang 8,  Min-Dian Li 9
Affiliations

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.

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