Exerkines, which are exercise-responsive signals released from various organs, are increasingly recognized as important mediators conferring the multiple metabolic benefits of regular physical activity. This review integrates recent preclinical and clinical evidence on how different types of exerkines, including peptide hormones and metabolites, coordinate interorgan crosstalk to regulate glucose and lipid metabolism, insulin sensitivity, and inflammation. It also highlights the development of exerkines-based diagnostics and therapeutics for precision management of chronic metabolic diseases.
The prevalence of chronic metabolic diseases has reached an epidemic proportion worldwide, driven largely by sedentary lifestyles and overnutrition. Exercise is increasingly recognized as a first-line, non-pharmacological intervention for preventing and treating multiple metabolic diseases, including type 2 diabetes (T2DM) and related cardiometabolic disorders. However, the clinical implementation of exercise is hindered by highly variable interpersonal responsiveness to exercise. Furthermore, the molecular transducers conferring the pleiotropic benefits of exercise remain poorly defined.
Professor Aimin Xu and Research Assistant Professor Leigang Jin from the State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, China, together with colleagues, address this gap in a review on “exerkines,” exercise-responsive signals that connect physical activity to systemic metabolic adaptation. The article was published in Volume 139, Issue 19 of the Chinese Medical Journal on October 05, 2026.
“ Exercise is not just about burning calories ,” said Prof. Xu. “ It triggers a coordinated molecular conversation across multiple organs through exerkines, comprising secreted polypeptides, host- and gut microbiome-derived metabolites, and other types of bioactive molecules .” Exerkines form a communication network linking skeletal muscle, adipose tissue, liver, and the gut, reshaping substrate use, endocrine function, and inflammatory tones in response to exercise intervention.
Interleukin-6 (IL-6) exemplifies how tissue origin and temporal dynamics shape biological outcomes. During exercise, skeletal muscle releases IL-6 in transient pulses that predominantly engage classical signaling via the membrane-bound IL-6 receptor (IL-6R) and gp130. In muscle, IL-6 acts in an autocrine manner to enhance glucose uptake, stimulate fatty acid oxidation, and support regeneration. Systemically, IL-6 also functions as an endocrine signal acting on adipose tissue, liver, gut, immune cells, and pancreatic islets to mobilize energy substrates, promote glucagon-like peptide 1 secretion, support insulin release, and attenuate inflammation, thereby improving insulin sensitivity. By contrast, in obesity and other chronic low-grade inflammatory states, IL-6 is produced largely by adipose tissue and preferentially signals through trans-signaling involving soluble IL-6R (sIL-6R) and gp130 across multiple cell types. This pattern is associated with persistent inflammation and insulin resistance in adipose tissue and liver, contributing to broader metabolic dysfunction.
The review also highlights the link between the liver-derived hormone fibroblast growth factor 21 (FGF21) and adipose tissue sensitivity. In obesity, circulating FGF21 levels increase, yet expression of its receptor FGFR1 and the coreceptor β-Klotho (KLB) declines in adipose tissue, contributing to FGF21 resistance. Exercise can restore adipose responsiveness by upregulating FGFR1 and KLB, strengthening its downstream signaling, and promoting adiponectin release. Adiponectin then acts as an endocrine mediator coordinating crosstalk among adipose tissue, liver, and skeletal muscle to support glucose and lipid homeostasis and improve whole-body insulin sensitivity.
Beyond protein exerkines, the authors also discuss exercise-responsive metabolites that contribute to systemic metabolic remodeling. For example, exercise-induced lactate can conjugate with phenylalanine to form N-lactoyl-phenylalanine (Lac-Phe), which has been linked to appetite suppression via central regulatory pathways. β-aminoisobutyric acid (BAIBA) promotes white adipose beiging and enhances hepatic fatty acid oxidation. The lipid metabolite 12,13-diHOME rises during exercise and increases skeletal muscle fatty acid uptake and oxidation to meet energetic demands, with preclinical studies suggesting additional links to cardiometabolic resilience. In the kidney, exercise promotes conversion of choline to betaine via choline dehydrogenase (CHDH). Betaine may dampen TANK-binding kinase 1 signaling, reduce cellular senescence and inflammation, and stimulate hepatic FGF21 production, thereby supporting glucose and lipid homeostasis.
Despite these advances, several challenges remain for translating exerkine biology into clinical practice. First, exerkines operate as an interacting network rather than individual factors alone, yet most studies only examine single molecules in isolation. Future work should clarify how exerkines coordinate or counterbalance each another, and how their intracellular pathways converge to drive metabolic adaptation. Second, direct comparisons across exercise modalities and intensities remain limited, constraining evidence-based personalization of exercise prescriptions. Third, poor or paradoxical responses in some individuals suggest a molecular phenotype of “exercise resistance,” underscoring the need for biomarkers that predict responsiveness and guide adjunct strategies. Finally, available data are insufficiently stratified by sex, age, and ethnicity, leaving important gaps in generalizability.
In summary, this Review synthesizes representative exerkines and exercise-responsive metabolites from skeletal muscle, liver, and adipose tissue, and outlines how inter-organ signaling helps maintain metabolic homeostasis. Further elucidation of exerkine interacting network, comparison of dynamic exerkine profiles across different ethnic populations, and clarification of sex dimorphism on exerkine physiology may help implement more effective, individualized strategies for precision management of chronic metabolic diseases. Identification of exercise-responsive pathways may also help to develop pharmacotherapies that amplify the benefits of physical activity for patients who fail to respond to lifestyle intervention alone.
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Reference
DOI: 10.1097/CM9.0000000000004200
About Professor Aimin Xu from The U niversity of Hong Kong, China
Professor Aimin Xu is affiliated with the Department of Medicine, School of Clinical Medicine, and serves as Director of the State Key Laboratory of Pharmaceutical Biotechnology at The University of Hong Kong. His laboratory pioneered the discovery and characterization of adipose- and liver-derived peptide hormones with diagnostic and therapeutic potential, translating key findings into clinical applications. He has published approximately 450 papers in leading journals, including Cell Metabolism , Nature Medicine , and Circulation , garnering over 55,000 citations and an H-index of 125. He holds more than 20 patents related to metabolic disease diagnostics and therapeutics.
About Research Assistant Professor Leigang Jin from The U niversity of Hong Kong, China
Dr. Leigang Jin is a Research Assistant Professor in the Department of Medicine, School of Clinical Medicine, The University of Hong Kong. He conducts sustained clinical and translational research on metabolic cardiovascular diseases, focusing on the FGF21/β-Klotho signaling axis in diabetic cardiomyopathy and atherosclerosis, and on FGF23/Klotho pathways in metabolic kidney-bone-cardiovascular disorders. He has published important findings as first author in journals including Circulation, Annual Review of Pharmacology and Toxicology, and EMBO Molecular Medicine, and received the prestigious The University of Hong Kong Outstanding Research Output Award. He also serves on the editorial board of Cardiovascular Toxicology.
Funding information
This work was supported by the National Key R&D Program of China (2022YFA0806102), the Areas of Excellence Scheme of the Research Grants Council of Hong Kong (AoE/M-707/18), the National Natural Science Foundation of China (82401011 and 82201449), and Shenzhen Natural Science Foundation in Basic Research Fund (JCYJ20250604180820027).
Chinese Medical Journal
Literature review
Not applicable
Exerkines in precision management of metabolic diseases
5-Oct-2026
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