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
  • 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: [email protected].
  • 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: [email protected].
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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