Exerkines in precision management of metabolic diseases

Abstract

Regular physical activity exerts systemic metabolic benefits that are pivotal for preventing and managing metabolic diseases. These effects are mediated in part by exerkines, which are signaling molecules released from various organs in response to exercise. Exerkines encompass polypeptides, nucleic acids, and bioactive lipids that collectively orchestrate metabolic adaptations. Recent metagenomic analyses have identified the gut microbiota as an additional source of exercise–responsive factors that modulate host metabolism and may influence individual responsiveness to training. Together, these diverse exerkines coordinate interorgan communication, enhance insulin sensitivity, maintain glucose and lipid homeostasis, and modulate inflammatory pathways. This review summarizes representative exerkines from skeletal muscle, adipose tissue, and liver, including interleukin-6, myostatin, fibroblast growth factor 21, adiponectin, and growth differentiation factor 15, which have shown promising therapeutic efficacy in preclinical studies and clinical trials for complex metabolic diseases. We also discuss microbiota-derived metabolites such as short-chain fatty acids that improve glucose and lipid metabolism, as well as host-derived metabolites including N-lactoyl-phenylalanine, betaine, and β-aminoisobutyric acid that regulate appetite, substrate utilization, and insulin action. Furthermore, we highlight recent progress in understanding how dynamic regulation of these exerkines mediates the metabolic benefits of exercise and their potential as targets for precision management of metabolic diseases. Understanding these molecular mediators of exercise provides a framework for integrating physical activity with pharmacological and nutritional strategies to improve metabolic health.

Introduction

Metabolic disorders and their complications pose a growing global health challenge in the context of sedentary lifestyles and an obesity epidemic.^[1,2] Regular physical activity is foundational to prevention and management across this disease spectrum.^[3] Landmark trials have demonstrated that intensive lifestyle interventions can reduce the progression to type 2 diabetes mellitus (T2DM) by about 58% in high-risk individuals.^[4] Among patients with established T2DM, structured exercise training improves glycemic control, enhances insulin sensitivity, and favorably modifies cardiovascular risk factors.^[3,5] However, the metabolic benefits of exercise show substantial heterogeneity across individuals. Some individuals exhibit dramatic improvements in glucose homeostasis and insulin sensitivity with training, whereas others, often termed “exercise nonresponders”, achieve only minimal metabolic gains.^[6] This variability highlights the need for precision exercise medicine, which integrates molecular insights to optimize exercise prescriptions for individual patients.^[7]

One emerging paradigm in exercise biology is the role of “exerkines”, exercise-responsive factors that mediate the systemic effects of physical activity.^[8] Almost all major organs, including skeletal muscle, adipose tissue, liver, heart, gut, brain, and bone, release bioactive molecules during exercise, extending the influence of muscle contractions to distal tissues through endocrine, paracrine, and autocrine signaling.^[8,9] Since the discovery in 2000 that contracting muscle releases interleukin-6 (IL-6) into circulation, hundreds of such exercise-induced signaling molecules have been identified.^[9,10] These exerkines encompass a wide array of molecules, including peptides, metabolites, lipid mediators, nucleic acids, and microbiome-derived factors. Collectively, they form a complex molecular network that fine-tunes metabolism and inflammation during and after exercise.^[8,9] Notably, several exerkines with potent metabolic actions, such as IL-6, fibroblast growth factor 21 (FGF21), and adiponectin, are being explored as therapeutic targets or exercise mimetics for management of chronic metabolic diseases, although the biology of many exerkines remains incompletely understood.^[11,12]

With advances in multi-omics technologies, the National Institutes of Health (NIH)-supported Molecular Transducers of Physical Activity Consortium (MoTrPAC) has begun to systematically map the molecular effects of exercise in both animals and humans.^[13,14] These integrative approaches reveal how physical activity reprograms tissues at the molecular level, uncovering mitochondrial remodeling, shifts in enzyme regulation through posttranslational modifications, and reorganization of intertissue signaling networks.

In this review, we synthesize current knowledge on representative exerkines derived from skeletal muscle, liver, and adipose tissue for the precision management of chronic metabolic diseases, and we highlight the molecular pathways by which these factors coordinate to control metabolic homeostasis through interorgan crosstalk. We also examine the gut microbiome as an exercise-responsive mediator that shapes the production of beneficial metabolites, modulates glucose and lipid metabolism, and potentially predicts individual responsiveness to exercise training. Furthermore, we discuss host-derived metabolite exerkines synthesized in skeletal muscle, adipose tissue, kidney, and other organs that recalibrate energy partitioning, appetite regulation, and insulin action. Building on these mechanistic insights, we explore how exerkine biology can be harnessed therapeutically for diabetes and related metabolic disorders, and how this knowledge may inform precision strategies that integrate exercise with pharmacologic and nutritional interventions.^[13,15,16]

Skeletal Muscle-derived Myokines as Exerkines

As one of the largest organs in the human body, skeletal muscle is not only the primary site for glucose disposal and energy expenditure during exercise but also a dynamic endocrine organ that releases numerous myokines into the circulation. Since the initial demonstration that acute exercise provokes IL-6 release from contracting fibers,^[10,17] dozens of exerkines derived from skeletal muscle have been identified.^[8,18,19] Although only a limited number have been thoroughly characterized, these myokines play pivotal roles in regulating metabolic health.

IL-6

The prototypical exercise-responsive myokine IL-6 is central to skeletal muscle communication with other organs in metabolic regulation.^[10] Acute endurance or interval exercise triggers a marked, intensity-dependent surge of IL-6 release from contracting muscle fibers.^[20] IL-6 then acts in both endocrine and autocrine manners to redistribute energy substrates by mobilizing fatty acids, preserving blood glucose availability, and stabilizing glycemia during the postexercise period.^[21–24] In humans, blockade of IL-6 signaling reduces exercise-induced secretion of glucagon-like peptide-1 (GLP-1) from intestinal L cells and pancreatic α cells, positioning IL-6 as a regulator of the incretin system.^[25] Pharmacologically elevating IL-6 to a level equivalent to exercise intervention slows gastric emptying and blunts postprandial glucose excursions, leading to glycemic control in T2DM.^[26,27] Beyond metabolism, IL-6 is required for other exercise benefits, including muscle repair through recruitment of regulatory T cells and exercise-induced cardiac adaptation.^[28,29]

Human intervention studies further indicate that IL-6 signaling contributes to exercise-mediated lipid mobilization and fat distribution, beyond improvements in cardiorespiratory fitness. In randomized trials, IL-6 receptor (IL-6R) blockade with tocilizumab prevented the typical reduction in visceral and cardiac fat in adults with abdominal obesity, despite preserved gains in aerobic fitness.^[24,30] Likewise, acute IL-6R blockade in both lean and obese men blunted the normal rise in free-fatty acids (FFAs) during exercise and recovery.^[31] More recent work indicates that selective suppression of basal IL-6 activity increases subcutaneous fat retention while decreasing adipose lipolysis and muscle fatty acid uptake.^[32] Taken together, these findings suggest that IL-6 activity, encompassing both transient surges during exercise and low-level tonic activity at rest, fine-tunes lipid metabolism across the exercise cycle and contributes to reduced ectopic fat deposition and improved insulin sensitivity in T2DM.

Although transient exercise-induced IL-6 exerts beneficial metabolic and anti-inflammatory effects, chronically elevated IL-6 derived from adipose tissue in obesity promotes inflammation and insulin resistance.^[33–35] Resting IL-6 levels are typically higher in obesity, whereas long-term exercise training lowers basal IL-6 and other inflammatory markers such as C-reactive protein (CRP).^[36] These apparently paradoxical observations can be reconciled by differences in IL-6 signaling modes. During transient, high-amplitude IL-6 pulses elicited by exercise, classical signaling through the membrane-bound IL-6 receptor (mIL-6R) and gp130 predominates, triggering regenerative and anti-inflammatory pathways.^[37] In contrast, in chronic inflammatory states, IL-6 activates trans-signaling through the soluble IL-6 receptor (sIL-6R) and gp130, favoring proinflammatory outcomes [Figure 1].^[38–41] Thus, exercise and chronic metabolic inflammation engage distinct IL-6 signaling profiles. In obesity, microbiome-derived leucine acts on white adipocytes to increase sIL-6R production, thereby amplifying IL-6 trans-signaling, promoting adipose inflammation, thus attenuating the metabolic benefits of exercise.^[42]

Figure 1.

Distinct metabolic actions of IL-6 during exercise and obesity. During physical activity, contracting skeletal muscle releases IL-6 that predominantly engages classic signaling through membrane IL-6R and gp130. IL-6 acts in an autocrine manner on muscle to enhance glucose uptake, stimulate fatty acid oxidation, and support muscle regeneration, and in an endocrine manner on adipose tissue, liver, gut, immune cells, and pancreatic islets to mobilize fuel and reduce inflammation, thereby improving insulin sensitivity. In obesity, adipose-derived IL-6 preferentially engages trans-signaling through sIL-6R together with gp130 on multiple cell types. Activation of IL-6 trans-signaling promotes chronic inflammation and insulin resistance in the liver and adipose tissue, thus exacerbating broad metabolic dysfunction. GLP-1: Glucagon-like peptide 1; IL-6: Interleukin-6; mIL-6R: Membrane-bound IL-6 receptor; sIL-6R: Soluble IL-6 receptor; TNF-α: Tumor necrosis factor-α. Created with BioRender.com.

The effects of IL-6 on organ function also vary by physiological and pathological context. In metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD), individuals with diabetes exhibit higher circulating markers of IL-6 trans-signaling, which correlate with more advanced liver fibrosis.^[43] Mendelian randomization suggests that lifelong reduction in IL-6 signaling, comparable to continuous pharmacologic IL-6 blockade, may increase the risk of fatty liver disease.^[44] Consistently, long-term IL-6R inhibition with tocilizumab can impair lipid handling despite reducing systemic inflammation.^[45] By contrast, preserving IL-6 and gp130 signaling appears hepatoprotective. Transient, exercise-like IL-6 pulses improve hepatic glucose and lipid metabolism and enhance resilience to steatosis.^[46] In practice, exercise programs that elicit short-lived IL-6 surges while lowering chronic inflammation may reduce hepatic fat and improve insulin sensitivity in individuals with T2DM and MASLD, whereas sustained IL-6 blockade may counteract these benefits in at-risk populations.^[47]

Therapeutic translation of these insights is challenging yet feasible. To capture the metabolic benefits of IL-6 while minimizing proinflammatory effects, researchers have developed cytokine chimeras that bias the signaling toward gp130-dependent pathways. For example, IC7Fc is a chimera that fuses IL-6 and ciliary neurotrophic factor domains to preferentially activate gp130 signaling. In mouse models of obesity and diabetes, IC7Fc enhances insulin sensitivity, stimulates GLP-1 secretion, reduces liver fat, and preserves muscle mass.^[48–51] These effects mimic key aspects of exercise-induced IL-6 signaling and provide a proof-of-concept evidence for therapeutic applications [Figure 1]. In contrast, broad long-term IL-6 inhibition in inflammatory disease has been associated with weight gain and adverse lipid changes, underscoring that some IL-6 activity is necessary for metabolic homeostasis.^[31,52,53] Looking forward, combining structured exercise that induces pulsatile IL-6 and incretin release with agents that steer IL-6 and gp130 signaling toward exercise-like profiles, rather than fully blocking the pathway, may enhance glycemic control and reduce hepatic fat while avoiding the drawbacks of complete IL-6 inhibition.

Myonectin

Myonectin, also called C1q/TNF-related protein 15 (C1QTNF15), is a myokine with a domain structure similar to adiponectin. It was first identified in cultured muscle cells and later shown to be inducible by exercise.^[54,55] In humans, several weeks of aerobic training can raise circulating myonectin levels, particularly in individuals with overweight or obesity.^[56–58] In mice, endurance exercise markedly upregulates myonectin expression in skeletal muscle, which in turn may drive systemic cardiometabolic adaptations.^[55] Trained wild-type (WT) mice exhibit smaller myocardial infarct size after ischemia-reperfusion (I/R) injury compared with sedentary controls, whereas this protection is lost in C1qtnf15 knockout (KO) mice. Conversely, transgenic overexpression of C1qtnf15 attenuates cardiac injury.^[59] Myonectin also protects against skeletal muscle atrophy and dysfunction, in part by activating the adenosine monophosphate (AMP)-activated protein kinase-peroxisome proliferator-activated receptor gamma coactivator 1-alpha signaling pathway (AMPK-PGC-1α) pathway, linking this myokine to mitochondrial remodeling and exercise responsiveness.^[60]

Myonectin also regulates interorgan lipid homeostasis. In cellular and animal models, it lowers circulating FFAs by promoting lipid uptake into adipocytes and hepatocytes, accompanied by increased expression of the lipid transport proteins cluster of differentiation 36 (CD36) and fatty acid transport protein 1 (FATP1).^[55,61] By reallocating fatty acids to tissues suited for storage or oxidation, myonectin limits ectopic lipid deposition and alleviates lipotoxic stress in the liver and muscle. Intracellularly, it activates metabolic pathways including protein kinase B (AKT) and AMPK signaling, stimulates mitochondrial biogenesis, and exerts antiapoptotic and anti-inflammatory effects in metabolic tissues.^[59,62] C1qtnf15 KO mice display impaired clearance of circulating lipids, elevated plasma triglycerides, and increased fat mass despite normal lipolysis.^[61] Interestingly, these KO mice develop less fatty liver than WT animals, likely due to the sequestration of excess fat in adipose tissue, underscoring myonectin’s role as a regulator of lipid allocation among tissues.^[55]

Sedentary lifestyles and obesity are associated with lower myonectin expression, whereas exercise can restore or increase its levels.^[62–64] Circulating myonectin level is inversely associated with metabolic risk factors, with its higher levels linked to lower body mass index (BMI) and greater insulin sensitivity.^[58,64,65] Through enhanced fatty acid utilization, improved mitochondrial function, and reduced inflammation, myonectin likely contributes to the insulin-sensitizing and lipid-lowering effects of regular exercise.^[57]

Taken together, myonectin emerges as a key link between exercise and metabolic health. As a training-inducible myokine, it redistributes lipids to tissues specialized for storage or oxidation, reduces lipotoxic stress in insulin-sensitive organs, and supports the resilience of cardiac and skeletal muscle.^[55,59] These coordinated actions provide a mechanistic basis connecting structured exercise with healthier fat distribution and improved glycemic control. Myonectin is therefore of interest both as a biomarker for training response and as a potential therapeutic target in the precision management of chronic metabolic diseases.^[64] Nevertheless, further studies in humans are still needed to define the magnitude and durability of exercise-induced changes in myonectin and to establish its causal role in mediating metabolic benefits.

Musclin

Musclin is a muscle-derived protein encoded by the OSTN gene and has recently been recognized as a mediator of endurance exercise adaptations. It shares structural homology with natriuretic peptides (NP) and contributes to the crosstalk between skeletal muscle and the heart. In mice, musclin shows increased mRNA and protein expression in skeletal muscle following aerobic exercise.^[66] Deletion of Ostn reduces exercise capacity and lowers the induction of mitochondrial enzymes and respiratory chain proteins in muscle.^[67–69] Restoring musclin in the KO mice with recombinant protein rescues muscle oxidative capacity and endurance performance. Ostn deficiency also attenuates the cardioprotective effect of training, as exercised KO mice fail to show the reduction in myocardial injury after I/R observed in WT animals. Conversely, infusion of a synthetic musclin peptide to a level comparable to that induced by exercise reproduces these cardioprotective effects in sedentary mice.^[68] Skeletal muscle-specific Ostn deletion worsens cardiac dysfunction induced by pressure overload, whereas muscle-specific Ostn overexpression mitigates it.^[70] Mechanistically, musclin enhances cardiac and skeletal muscle function through NPs signaling. By binding the clearance receptor (NPR-C), it reduces peptide clearance and strengthens C-type natriuretic peptide (CNP) signaling. In the heart, this raises cardiac cAMP and protein kinase A (PKA) activity to improve contractility and increases protein kinase G (PKG) activity in fibroblasts to limit fibrosis. In skeletal muscle, activation of PKA and PKG promotes cAMP-driven induction of PGC-1α and mitochondrial biogenesis during endurance exercise, thereby supporting both cardiac and skeletal muscle adaptations.^[66,70,71]

Intriguingly, musclin’s role in metabolism is context-dependent. Transient rises during exercise are adaptive, whereas sustained elevation may have adverse consequences. In mice, long-term musclin overexpression acts as a brake on energy expenditure, suppressing the browning of white adipose tissue and impairing thermogenesis through a pathway involving transferrin receptor 1 (TfR1) and PKA signaling.^[72] Mice with muscle-specific Ostn overexpression show reduced thermogenic gene expression in adipose tissue, greater weight gain on a high-fat diet (HFD), and worse insulin resistance, whereas Ostn deficiency produces the opposite pattern with more beige fat, less weight gain, and improved metabolic indices.^[72] Musclin expression is also sensitive to ambient temperature and inversely correlated with adaptive thermogenesis, suggesting that high musclin levels may hinder energy expenditure and promote metabolic dysfunction in sedentary or obese states.^[72]

In a cross-sectional study, circulating musclin correlated positively with fasting insulin, homeostatic model assessment of insulin resistance (HOMA-IR), and visceral adiposity, independent of BMI and cardiorespiratory fitness, indicating a link with insulin resistance in adults with obesity.^[73] Collectively, these observations suggest that exercise-induced musclin pulses support mitochondrial function and cardiac resilience, whereas chronically elevated musclin in the context of physical inactivity or obesity may impair glucose and lipid metabolism. Defining the optimal dose, timing, and tissue context will be essential for translating musclin biology into strategies for precision management of T2DM. Training programs that amplify exercise-induced musclin pulses while lowering basal levels may preserve cardiometabolic benefits without compromising adipose thermogenesis.^[73,74]

Myostatin

Unlike other myokines with favorable metabolic effects, myostatin, encoded by the MSTN gene and also known as growth differentiation factor 8 (GDF8), is a muscle-derived factor that restricts muscle mass and negatively influences metabolism. Myostatin is a member of the transforming growth factor-β (TGF-β) family that acts as a potent inhibitor of muscle growth.^[75,76] Loss-of-function variants in animals and humans lead to marked muscle hypertrophy and hyperplasia with reduced fat mass.^[77] Mechanistically, mature myostatin protein binds to activin type II receptors (ActRIIA/B) on muscle fibers, recruits activin receptor-like kinases 4 and 5 (ALK4/5), and activates SMAD2/3 signaling, which suppresses protein synthesis and promotes protein degradation.^[78–80] Elevated myostatin levels are frequently observed in obesity, T2DM, and metabolic syndrome.^[81] Consistently, Mstn KO mice show improved insulin sensitivity and glucose tolerance, whereas muscle-specific overexpression of Mstn induces insulin resistance.^[82,83] Myostatin thus provides a molecular link between reduced muscle mass and metabolic dysfunction.

Exercise suppresses myostatin signaling and promotes healthier muscle and metabolic profiles. Both endurance and resistance training reduce myostatin expression in muscle while simultaneously increasing follistatin, a liver- and muscle-derived antagonist that binds to myostatin and prevents receptor activation.^[84,85] Acute exercise induces transient increases in circulating follistatin, and regular training maintains elevated baseline levels, neutralizing myostatin activity. With reduced myostatin signaling, muscle protein synthesis and regeneration proceed more effectively, facilitating hypertrophy and enhancing insulin sensitivity.^[86] This mechanism helps explain why physically active individuals typically preserve lean mass and maintain metabolic health, whereas sedentary individuals with metabolic syndrome often exhibit elevated myostatin that declines with exercise or weight loss interventions.

The central role of myostatin in regulating muscle mass and metabolism has made it an attractive therapeutic target. Several inhibitors for myostatin have entered clinical trials. Trevogrumab (REGN1033), a monoclonal antibody that binds to the precursor and mature myostatin with high specificity, prevents downstream signaling with minimal crossreactivity to GDF11.^[87] Although the initial trial for muscle-wasting disorders showed limited efficacy as monotherapy, it is now being evaluated as a potential therapeutic option for obesity-related metabolic comorbidities. In 2025, a Phase 2 trial reported that trevogrumab combined with the GLP-1 receptor agonist semaglutide produced significantly greater fat loss while preserving lean mass compared with semaglutide alone.^[87] The largest gains were achieved with triple therapy using semaglutide, trevogrumab, and the activin A blocking antibody garetosmab, which preserved lean mass during weight loss and produced greater fat reduction than semaglutide alone.^[87]

Bimagrumab (BYM-338) is another monoclonal antibody that blocks ActRII, thereby inhibiting signaling from myostatin and related ligands such as activins and GDF11. It has been tested in sporadic inclusion body myositis and age-related sarcopenia, consistently increasing muscle mass, although translating this into functional improvement has been difficult.^[88,89] More recently, in a 48-week trial in adults with obesity and T2DM, bimagrumab reduced fat mass, increased lean mass, and improved glycemic control, highlighting the potential of ActRII blockade for metabolic disease.^[90]

Several next-generation inhibitors are advancing, including GYM329 (RO7204239), which shows robust muscle growth in preclinical models.^[91] Apitegromab (SRK-015) has improved motor function in patients with spinal muscular atrophy and shown a favourable safety profile in clinical studies.^[92,93] Future pharmacological benefits include ensuring that increased muscle mass translates into durable functional and metabolic gains. Combining these agents with structured exercise, nutritional optimization, or incretin-based therapies such as GLP-1 receptor agonists may offer powerful strategies for precision management of obesity, T2DM, and related disorders.

In sum, contracting skeletal muscle releases a suite of exerkines that orchestrate systemic metabolic adaptations. IL-6 acutely augments insulin secretion and exerts anti-inflammatory effects.^[48] Myonectin promotes lipid clearance and oxidation.^[59] Musclin enhances endurance capacity and influences insulin sensitivity,^[67] whereas downregulated myostatin by exercise relieves its constraints on muscle growth and glucose uptake.^[84]

Adipose and Liver-secreted Exerkines

Although skeletal muscle is a major source of exerkines, exercise also elicits important endocrine signals from the adipose tissue and liver, two important organs in energy storage and metabolic regulation. During and after physical activity, these tissues secrete adipokines and hepatokines that enhance insulin sensitivity, improve lipid handling, and attenuate inflammation.^[94,95] Among a large number of adipokines and hepatokines, several factors are particularly relevant to the metabolic benefits of exercise, including adiponectin, FGF21, and growth differentiation factor 15 (GDF15).^[8]

Adiponectin

Adiponectin, an adipokine encoded by the ADIPOQ gene and secreted predominantly by adipocytes, exerts broad metabolic effects, including insulin-sensitizing, anti-inflammatory, and cardioprotective actions.^[95] It binds to three receptors, including adiponectin receptor 1 (AdipoR1), AdipoR2, and T cadherin, which are widely expressed across tissues, and this engagement activates several downstream pathways such as AMPK and peroxisome proliferator activated receptor alpha (PPARα).^[96,97] Unlike most adipokines that rise with increasing fat mass, adiponectin concentrations are paradoxically low in obesity and T2DM.^[98,99] Circulating adiponectin is inversely related to adiposity and metabolic health, with lower levels linked to poorer glycemic control, adverse lipid profiles, and insulin resistance.^[100] In animal models, loss of Adipoq worsens obesity-related insulin resistance, whereas infusion or genetic overexpression improves insulin sensitivity.^[101–103] Similarly, pharmacologic approaches such as the adiponectin receptor agonist AdipoRon improve glucose tolerance and insulin sensitivity in obese mice.^[104]

Numerous studies in humans and animals show that aerobic training raises circulating concentrations.^[105] Meta-analyses indicate that regular aerobic exercise produces significant increases, especially in higher intensity programs and in populations with low baseline adiponectin, such as children with obesity and adults with prediabetes or diabetes.^[106] Notably, adiponectin rises with exercise even in the absence of weight loss, underscoring that physical activity itself promotes its production.^[106] When exercise is accompanied by weight loss, adiponectin increases further, and combined lifestyle interventions often produce greater long-term adiponectin increases than exercise alone.^[107] Thus, regular exercise, independent of weight reduction, strongly enhances adiponectin and likely contributes to the improvement in insulin sensitivity.

In mice, voluntary running improves cardiac function in wild-type (WT) animals but not in Adipoq KO mice, indicating that adiponectin is necessary for exercise-induced improvements in cardiac functions.^[108,109] Adiponectin also contributes to the neurobiological effects of exercise training. In mice, exercise increases hippocampal neurogenesis and reduces depression like behavior, whereas Adipoq-deficient mice do not show these benefits, partly due to impaired activation of AMPK in the hippocampus.^[110] Likewise, lack of adiponectin blunts exercise-induced AMPK phosphorylation in skeletal muscle and prevents the usual rise in IL-6 during exercise.^[111] Taken together, these findings identify adiponectin as a key mediator enabling cardiovascular, metabolic, and neuroprotective adaptations to training.

Pharmacological augmentation of adiponectin signaling recapitulates many benefits of exercise. Adiponectin receptor agonists such as AdipoRon and its mimetic peptides, such as ADP355, improve insulin actions and alleviate obesity-related complications in preclinical models.^[104,112] Moreover, both agents reduce hepatic lipid contents and inflammation while improving insulin sensitivity and mitochondrial function in mouse models with MASLD.^[112] In diabetic mice, chronic AdipoRon treatment improves cognition and neuroplasticity, with increased hippocampal synaptic markers.^[113] AdipoRon treatment also enhances myocardial fuel oxidation and reduces fibrosis, consistent with the protective role of exercise.^[114] Notably, acute administration of adiponectin to rodents increases glucose uptake and fatty acid oxidation in skeletal muscle, effectively mimicking the metabolic effects of a single exercise session.^[115] The GLP-1 receptor agonists have shown to increase adiponectin levels in experimental models and in patients with diabetes, suggesting that the therapeutic effects of GLP-1 agonism is attributed in part to elevated adiponectin.^[116] Ongoing research is advancing adiponectin receptor agonists and pathway activators as potential exercise mimetics, though further clinical trials are needed to confirm efficacy in humans.

FGF21

FGF21 is a hormone produced primarily by the liver and has emerged as a central regulator of energy balance and a mediator of exercise-induced metabolic benefits.^[117] It acts through a receptor complex composed of fibroblast growth factor receptor 1c (FGFR1) and the coreceptor β-Klotho (KLB).^[118] KLB is expressed mainly in metabolically active tissues such as liver, adipose tissue, pancreas, and certain brain regions, which determine the target selectivity of FGF21. The binding of FGF21 to the FGFR1–KLB complex activates several downstream signaling pathways, including the mitogen-activated protein kinase (MAPK) cascade, particularly extracellular signal-regulated kinase 1/2 (ERK1/2).^[119,120] In obese rodents, FGF21 treatment ameliorates hyperglycemia, dyslipidemia, fatty liver, atherosclerosis, and cardiac dysfunction, underscoring its value as both a biomarker and therapeutic target.^[121–123]

FGF21 and adiponectin are functionally interconnected. In mice, FGF21 stimulates adipocyte secretion of adiponectin, which serves as an indispensable downstream effector of FGF21 signaling.^[121,122] Several metabolic actions of FGF21 in mice, including improvements in insulin sensitivity and reductions in hepatic fat, are diminished in the absence of adiponectin. Likewise, multiple clinical trials on long-acting FGF21 analogs in individuals with obesity, T2DM, and MASLD have consistently observed marked increases in circulating adiponectin alongside reductions in liver fat, inflammation, and fibrosis.^[124–126]

Exercise has a complex effect on FGF21 levels. Acute endurance or high-intensity exercise induces a transient spike in circulating FGF21 in both rodents and humans.^[127,128] By contrast, long-term exercise often lowers baseline FGF21 in individuals with obesity or in older adults.^[129,130] This paradox of exercise on circulating FGF21 may reflect obesity-associated FGF21 resistance, characterized by reduced responsiveness in adipose tissue due to downregulation of FGFR1 and KLB.^[131,132] Exercise appears to alleviate this resistance by inducing FGFR1 and KLB expression in adipose tissue, partly through PPARγ activation, which increases the tissue sensitivity to FGF21 [Figure 2].^[132] Mice lacking Klb in adipose tissue fail to exhibit training-induced improvements in insulin resistance, glucose tolerance, adiponectin secretion, or resolution of adipose inflammation.^[133] Similarly, global Fgf21 KO mice show blunted improvements in glucose homeostasis under HFD feeding, although they still benefit from exercise’s anti-inflammatory effects.^[132]

Figure 2.

Exercise restores FGF21 sensitivity and multiorgan crosstalk to counteract obesity-related metabolic dysfunction. In obesity, hepatic FGF21 secretion into the circulation is elevated, whereas expression of its receptor FGFR1 and the coreceptor β-Klotho (KLB) in adipose tissue is reduced, resulting in “FGF21 resistance”. Exercise resensitizes adipose tissue to FGF21, augments downstream signaling, and increases adiponectin release into the circulation by inducing adipose expression of FGFR1 and KLB. Adiponectin acts in an endocrine manner to coordinate interorgan crosstalk among adipose tissue, liver, and skeletal muscle to maintain glucose and lipid homeostasis and improve systemic insulin sensitivity. FGF21: Fibroblast growth factor 21; FGFR1: Fibroblast growth factor receptor 1. Created with BioRender.com.

FGF21 also mediates exercise-induced remodeling of adipose tissue. Increases in FGF21 during exercise or cold exposure promote browning of white adipose tissue by upregulating uncoupling protein 1 (UCP1) and other thermogenic genes, thereby elevating energy expenditure.^[134,135] Exercise-induced FGF21 is required for this adaptation, as mice lacking Fgf21 show reduced beige fat induction and gain more weight on a HFD despite training.^[132] Mechanistically, FGF21 promotes browning through activation of PPARγ and PGC-1α, and it may act synergistically with other exercise factors such as irisin.^[136] In addition, FGF21 shifts substrate utilization by stimulating lipolysis in white adipose tissue and increasing fatty acid oxidation in the liver and skeletal muscle.^[117] These actions reduce ectopic lipid deposition and improve plasma lipid profiles, supporting a protective role of FGF21 against hepatic steatosis and dyslipidemia.

Exercise also sensitizes FGF21 actions in the heart. Under sedentary conditions, adult cardiomyocytes express a rather low level of KLB and respond weakly to FGF21.^[137] Endurance training markedly increases cardiac KLB expression, enabling FGF21 to activate a signaling axis involving AMPK–forkhead box O3 (FOXO3)–sirtuin 3 (SIRT3) in the heart. This preserves mitochondrial function and protects against diabetic cardiomyopathy.^[137] In diabetic mice, exercise-induced improvements in cardiac function, fibrosis, and angiogenesis are abolished when FGF21 signaling is blocked by cardiomyocyte-specific Klb deletion or by global Fgf21 KO.^[138,139] Enhanced cardiac and adipose sensitivity to FGF21 is therefore a central mechanism mediating the metabolic and cardiovascular benefits of exercise.

Given its pleiotropic effects, the development of FGF21-based pharmacotherapies is advancing rapidly. Several long-acting FGF21 analogs, including pegbelfermin,^[140] efruxifermin,^[141] and pegozafermin,^[126] have shown efficacy in Phase 2 and 3 trials for MASLD and related metabolic conditions. These agents consistently reduce liver fat and fibrosis, improve lipid profiles, and increase circulating adiponectin in patients with obesity and fatty liver disease. Therefore, FGF21 agonists can be potentially used as a potent exercise mimetic for the management of multiple metabolic morbidities.

GDF15

GDF15, also known as macrophage inhibitory cytokine-1 (MIC-1), is a stress-responsive cytokine increasingly recognized as an important metabolic regulator. Unlike classical metabolic hormones from defined glands, GDF15 is produced by diverse cell types under various stress.^[142] Its actions are mediated by the glial cell line-derived neurotrophic factor family receptor alpha-like (GFRAL), which is expressed mainly in the brainstem, particularly in the area postrema and the nucleus of the solitary tract. When GDF15 binds to GFRAL in partnership with the coreceptor rearranged during transfection (RET), it activates neural circuits that suppress appetite and alter energy expenditure.^[143] Pharmacologic elevation of GDF15 reduces food intake and body weight while improving glucose and insulin sensitivity. Conversely, genetic deletion of Gdf15 or its receptor Gfral increases food intake and weight gain, particularly on high-calorie diets.^[144] Furthermore, GDF15 helps sustain energy expenditure during caloric restriction by activating GFRAL-dependent sympathetic pathways, which promote fat oxidation and muscle thermogenesis, thereby limiting the decline in metabolic rate during dieting.^[142]

Exercise is a potent inducer of GDF15. In humans, vigorous or prolonged exercise (e.g., marathon running) elicits marked increases in circulating GDF15, making it among the most strongly upregulated plasma proteins in response to exercise intervention.^[145–147] Acute endurance exercise elevates GDF15 alongside increases in FFA, suggesting that GDF15 may help mobilize fats to be used as fuel. A likely mechanism involves GFRAL-mediated sympathetic activation of adipose tissue in promoting lipolysis and lipid utilization.^[148] In patients with T2DM, larger exercise-induced GDF15 spikes have been associated with greater improvements in β-cell function and glycemic control after training.^[149] In contrast, chronically elevated GDF15 is common in obesity, insulin resistance, and T2DM, possibly as a compensatory response to metabolic stress.^[150] Long-term training in sedentary individuals with obesity lowers baseline GDF15, likely reflecting reductions in systemic inflammation and cellular stress.^[151] Thus, exercise regulates GDF15 dynamically, producing acute surges that facilitate fuel mobilization and chronic reductions reflecting improved metabolic health.

The levels of GDF15 reached during exercise remain within a physiological range and do not elicit the adverse effects observed with pharmacologic dosing. High-dose GDF15 administration in sedentary mice causes anorexia and reduced activity, consistent with nausea-like behavior.^[152] In contrast, exercise-induced elevations in humans and animals do not suppress appetite or motivation, underscoring that GDF15 functions as an adaptive stress signal during physical activity rather than as a sickness hormone.^[152]

The promising metabolic effects of GDF15 have prompted its therapeutic exploration. Several engineered GDF15 analogs are in clinical development, with mixed but encouraging results. MBL-949, a long-acting analog, produced modest weight loss in a Phase 2 trial in obesity,^[153] whereas LY3463251 achieved small weight reductions in a Phase 1 study.^[154] More recently, JNJ-9090 (CIN-109) demonstrated robust, dose-dependent weight loss in a Phase 1 trial, with the highest doses also increasing lean mass.^[155] These early phase clinical trial outcomes highlight the potential of targeting GDF15 pathways. Ongoing trials in obesity-related T2DM are expected to address whether GDF15 agonism can safely provide durable weight loss and metabolic benefits beyond weight reduction.

Gut Microbiome as a Mediator of Exercise-Induced Metabolic Benefits

Exercise not only modulates host tissues but also remodels the gut microbiome, which in turn influences systemic metabolism. Athletes and other highly active individuals typically display greater microbial diversity and an enrichment of taxa involved in carbohydrate and amino acid metabolism compared with sedentary individuals.^[156–158] Training interventions can alter microbiome composition and function even without concurrent changes in diet or body weight.^[159] Evidence from rodent models and human studies indicates that sustained exercise generally increases microbial diversity and enriches health-promoting taxa, although results vary due to strong influences from diet, geography, and environment.^[160] Despite heterogeneity at the species level, functional signatures linked to metabolic benefit are more reproducible across studies.

One prominent class of microbial metabolites enhanced by exercise is short-chain fatty acids (SCFAs), particularly butyrate.^[160,161] Butyrate, produced by fiber fermenting bacteria such as Faecalibacterium and Roseburia, serves as a primary fuel for colonocytes and confers systemic benefits.^[162] Elevated butyrate levels in athletes and exercised animals are associated with improved metabolic profiles.^[163] SCFAs strengthen gut barrier integrity, reduce endotoxin leakage, lower systemic inflammation, and regulate glucose and lipid metabolism.^[164] By activating free-fatty acid receptor 2 (FFAR2) and FFAR3 on intestinal L cells, SCFAs also stimulate secretion of GLP-1 and peptide YY, enhancing insulin release and satiety.^[165] Transplantation of microbiota from exercised mice into sedentary germ-free animals increases colonic butyrate, elevates GLP-1, and improves glucose tolerance, demonstrating that exercise-induced microbial changes can directly mediate glycemic benefits.^[166]

There is growing evidence suggesting that gut microbiota also modulates lactate level, which in turn affects exercise efficacy. During strenuous activity, muscle-derived lactate enters the gut lumen where certain microbes metabolize it.^[167] Veillonella species consume lactate and generate propionate, and their abundance is elevated in endurance athletes. Administration of Veillonella or propionate to mice enhances endurance performance.^[167] Similarly, Bacteroides uniformis (B. uniformis) abundance inversely correlates with race times in athletes, and supplementation in mice prolongs exercise capacity while increasing SCFA production and gluconeogenic gene expression.^[168] A pilot trial using the prebiotic α-cyclodextrin to enrich B. uniformis reported modest improvements in endurance metrics.^[168] Exercise also increases microbial metabolites such as fatty acid amides that stimulate sensory neurons and elevate dopamine in reward circuits, potentially reinforcing exercise motivation.^[169] These shifts depend on exercise intensity and duration and often regress when training ceases, as shown in a human trial where gains in SCFA production and bacterial diversity diminished after 6 weeks of detraining.^[159]

Emerging research links the gut microbiome to interindividual variability in metabolic responses to exercise. In a randomized controlled trial of men with prediabetes, 12 weeks of high-intensity interval training (HIIT) improved glycemic traits on average, but outcomes differed between responders and nonresponders.^[6] Responders showed increases in bacterial taxa within Firmicutes, Bacteroidetes, and Proteobacteria that produce SCFAs or degrade branched-chain amino acids (BCAA), whereas nonresponders shifted toward less favorable pathways. When fecal microbiota from these groups were transplanted into obese mice, recipients of responder microbiota improved glycemic control and insulin sensitivity, whereas recipients of nonresponder microbiota did not.^[6] Supplementation with SCFAs partially rescued the metabolic phenotype in mice colonized with nonresponder microbiota, implicating SCFA production as a key mechanism. In murine models of heart disease, microbiota from exercised donors enhanced recovery after myocardial infarction compared with microbiota from sedentary donors, accompanied by altered levels of microbial phenolic acids, including 3-hydroxyphenylacetic acid (3-HPA) and 4-HPA.^[170] Consistent findings from two independent human trials indicate that more connected and robust baseline gut microbial networks predict larger improvements in liver fat and insulin sensitivity with training.^[171,172] Although the specific microbial mediators are still being defined, the current evidence indicates that the gut microbiome modulates both the effectiveness of exercise and the magnitude of its metabolic benefits.

Exercise training remodels the gut microbiome in ways that promote metabolic health by increasing beneficial metabolites such as SCFAs, strengthening gut barrier integrity, and modulating signals that improve glucose and lipid metabolism while supporting cardiovascular function. An individual’s microbiome profile may help predict metabolic responsiveness to exercise, creating an opportunity to use microbiome assessments to guide personalized prescriptions. For individuals who do not respond robustly to training, adjunct strategies that target the microbiome, including selected probiotics, prebiotic fibers, or SCFA supplementation, may help unlock the metabolic benefits of physical activity.^[6]

A recent study further identifies sIL-6R as a key exerkine determining the exercise efficacy in improving insulin sensitivity and glycemic control. In individuals with overweight/obesity who underwent a 12-week exercise intervention, circulating sIL-6R level displays dichotomous alterations between exercise responders and nonresponders. In nonresponders, elevated gut microbiome-derived leucine acts on adipocytes to induce disintegrin and metalloproteinase 17 (ADAM17)-mediated sIL-6R production through the mammalian target of rapamycin (mTOR)–hypoxia-inducible factor 1α (HIF-1α) pathway, which in turn impairs the metabolic benefits of exercise through IL-6 trans-signaling-induced adipose inflammation. Notably, blockade of adipocyte ADAM17 by genetic disruption or neutralization of sIL-6R restores the efficacy of exercise-shaped gut microbiome from nonresponders in improving glucose tolerance and insulin sensitivity in obese mice.^[42] Recognizing the microbiome as both an effector and a predictor of exercise responses opens a new frontier against complex metabolic disease and underscores that gut bacteria are key partners in the benefits of exercise.^[173]

Metabolite Exerkines in the Crosstalk of Exercise and Metabolism

Beyond proteins, peptide hormones, microbiota, and microbial metabolites, a distinct class of host-derived metabolite acting as exerkines has gained increasing attention. These small molecules are synthesized in skeletal muscle, liver, adipose tissue, and kidney, rise within minutes to hours in proportion to exercise intensity, and signal through G protein-coupled receptors (GPCRs) and metabolic kinases to recalibrate appetite, fuel utilization, and insulin action across different organs.^[174] Representative examples include N-lactoyl-phenylalanine (Lac-Phe),^[175,176] betaine,^[177] β-aminoisobutyric acid (BAIBA),^[178] and 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME).^[179]

Lac-Phe

Lac-Phe is a highly conserved exercise-induced metabolite generated by carnosine dipeptidase 2 (CNDP2)-mediated reverse proteolysis that conjugates lactate and phenylalanine.^[176] It rises robustly after acute exercise across species, including mice, racehorses, and humans, and is among the most elevated circulating metabolites immediately after exercise.^[176] Pharmacologic administration of Lac-Phe suppresses food intake in obese mice without reducing physical activity or energy expenditure, and repeated dosing lowers fat mass, body weight, and blood glucose. Disruption of Cndp2 blunts postexercise appetite suppression and the anti-obesity benefits of training, establishing Lac-Phe as a crucial link between exercise and weight regulation. Neurocircuit analyses reveal that Lac-Phe inhibits hypothalamic agouti-related peptide (AgRP) neurons through ATP-sensitive potassium (KATP) channel activation, with secondary engagement of paraventricular neurons contributing to appetite suppression.^[175] A single endurance session can raise plasma Lac-Phe to low micromolar concentrations comparable to effective experimental exposure.^[180]

At the population level, Lac-Phe increases in proportion to exercise intensity, and higher-intensity aerobic exercise elicits larger, more sustained elevations accompanied by broader metabolomic remodeling.^[176] In adults with overweight or obesity, larger acute rises in Lac-Phe predict greater reductions in abdominal fat during training, particularly in subcutaneous depots, supporting its potential as a biomarker for precision exercise prescriptions.^[181] Beyond exercise, both metformin and feeding increase Lac-Phe in humans.^[182] Mechanistic studies show that metformin inhibits mitochondrial complex I, which raises glycolytic lactate and stimulates CNDP2-dependent biosynthesis of Lac-Phe.^[182] Disrupting Lac-Phe production markedly blunts metformin-induced reductions in food intake and body weight, identifying Lac-Phe as a downstream mediator of this pathway. At the tissue level, CNDP2 expressed in epithelial and immune cells likely contributes to Lac-Phe generation under metabolic or pharmacologic stimulation. Renal transporters appear to facilitate Lac-Phe excretion, and variation within the solute carrier 17 (SLC17A) family correlates with urinary levels, with acute sprinting also increasing urinary Lac-Phe.^[183] In preclinical models, deletion of selected renal transporters reduces urinary but not plasma Lac-Phe, suggesting partial separation between plasma and urinary pools and highlighting practical considerations for sampling and interpretation when Lac-Phe is used as a biomarker.^[183]

Betaine

Betaine (trimethylglycine) is a choline-derived metabolite that also responds to exercise and exerts broad metabolic effects. Unlike myokines derived from muscle, betaine is produced primarily in the kidney during physical activity.^[177] Endurance training increases renal choline dehydrogenase (CHDH) expression, promotes conversion of choline to betaine, and raises circulating betaine levels in proportion to exercise duration.^[184] Sedentary and obese states are associated with reduced tissue betaine stores, whereas long-term training restores these levels, and plasma betaine correlates positively with aerobic training volume.^[185] Mechanistically, betaine serves as a methyl donor and osmolyte, and also modulates metabolic signaling pathways. It directly binds and inhibits TANK-binding kinase 1 (TBK1), a stress kinase implicated in chronic inflammation and insulin resistance.^[177] By attenuating this pathway, betaine reduces nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and cellular senescence in metabolic tissues, enhances thermogenesis, and improves insulin signaling.^[177] In parallel, betaine stimulates hepatokine secretion, notably FGF21 from the liver and adipose tissue, which promotes adiponectin release and fatty acid oxidation.^[186] In obese mice, dietary betaine prevents insulin resistance and fatty liver, accompanied by increased energy expenditure and adipose browning. These effects are diminished in Fgf21-deficient mice, highlighting the importance of the betaine–FGF21 axis in mediating its metabolic actions.^[186]

Insufficiency of betaine is linked to metabolic dysfunction. Individuals with insulin resistance and T2DM often exhibit lower plasma betaine, and the degree of deficiency correlates with the severity of insulin resistance.^[187,188] Conversely, increasing betaine through exercise, diet such as beetroot and whole grains, or supplementation can reproduce several benefits of physical training. In HFD models, betaine improves hepatic function, normalizes lipid metabolism, and reduces triglyceride accumulation and inflammation, improving glycemic control.^[189] From a translational perspective, betaine is already available as an oral supplement and its potential as an exercise mimetic is gaining recognition.^[190] Recent preclinical studies show that betaine supplementation in aged mice reproduces several benefits of exercise, including reduced hepatic steatosis, improved muscle function, enhanced cognition, and delayed age-related metabolic decline.^[177] Small clinical studies indicate modest glucose-lowering effects, although larger trials are needed.^[191,192] Overall, current evidence positions betaine as both a mediator and amplifier of exercise-induced metabolic benefits, offering promise as an adjunct therapy for metabolic disease and a potential enhancer of structured exercise programs.

BAIBA

BAIBA is a nonprotein amino acid that functions as a myokine-like metabolite linking exercise to systemic metabolic remodeling.^[193] It is produced in skeletal muscle through a pathway partly dependent on PGC-1α activation. During exercise, particularly under endurance conditions that activate PGC-1α, BAIBA release from myocytes increases.^[178] Biochemically, BAIBA exists as two enantiomers, R- and S-BAIBA, derived from thymine and valine catabolism, respectively. Exercise primarily increases L-β-aminoisobutyric acid (L-BAIBA) derived from valine metabolism, reflecting enhanced BCAA oxidation in active muscle.^[194] Once being released, BAIBA acts on adipose tissue and the liver to promote metabolic health. It stimulates browning of white adipose tissue and increases hepatic fatty acid oxidation, driving adipocytes toward a mitochondria-rich thermogenic phenotype characterized by elevated UCP1 expression.^[178] Through these coordinated actions, BAIBA supplementation in mice attenuates diet-induced obesity, reduces visceral fat accumulation, and improves insulin sensitivity without affecting food intake. BAIBA-treated mice show increased energy expenditure and a shift toward fatty acid utilization as fuel, consistent with an exercise-trained phenotype.^[178] Importantly, BAIBA-driven fat loss is achieved without suppressing appetite, highlighting its role in fuel partitioning and thermogenesis rather than caloric restriction.

When the BAIBA pathway is impaired, some of the metabolic benefits of exercise are diminished. Inhibition of PGC-1α reduces BAIBA production and attenuates exercise-induced metabolic benefits, whereas genetic variation in alanine-glyoxylate aminotransferase 2 (AGXT2) influences circulating BAIBA levels and may modulate BAIBA-dependent metabolic responses.^[195] Clinically, lower circulating BAIBA levels correlate with adverse metabolic traits, including higher fasting glucose, insulin, and triglycerides, whereas physically active individuals exhibit stronger BAIBA responses correlating closely with the improvement in insulin sensitivity.^[196] These observations identify BAIBA as a central mediator of exercise-induced metabolic adaptation by promoting adipose browning and fatty acid oxidation.

Translationally, BAIBA is being explored as a prototype exercise mimetic that activates AMPK and PPARα/δ signaling in the liver and adipose tissue through a distinct nonhormonal mechanism.^[197] Although clinical evidence remains limited, BAIBA or BAIBA-inducing therapies may complement exercise by enhancing fat oxidation and energy expenditure in individuals with diabetes or metabolic syndrome. Circulating BAIBA may also serve as a biomarker for exercise responsiveness, as greater increases predict stronger anti-obesity and insulin-sensitizing effects.^[197]

12,13-diHOME

Exercise modifies circulating lipids that function as metabolic signals. Among them, 12,13-diHOME, a fatty acid derivative released from brown adipose tissue during exercise, plays a key role in communication between brown fat, skeletal muscle, and the cardiovascular system.^[198,199] Individuals with higher aerobic fitness exhibit greater exercise-induced increases in 12,13-diHOME, which correlate with improved insulin sensitivity and lower circulating lipids, whereas low baseline concentrations are associated with adverse cardiovascular risk markers. Mechanistically, 12,13-diHOME promotes fatty acid uptake and oxidation in skeletal muscle, thereby enhancing fuel availability during exercise.^[198] Animal studies also show that increasing circulating 12,13-diHOME through cold exposure or brown fat transplantation improves cardiac function and overall metabolic health. Although further studies are needed, 12,13-diHOME exemplifies how lipid-derived exerkines contribute to muscle performance and cardiometabolic resilience.

Together, metabolite exerkines represent an underappreciated emerging biochemical axis through which physical activity remodels systemic metabolism. Acting within a tightly coordinated network, molecules such as Lac-Phe, betaine, BAIBA, and 12,13-diHOME integrate cues from muscle, liver, adipose tissue, and kidney to recalibrate energy partitioning, appetite regulation, and insulin action [Figure 3]. Their rapid, intensity-dependent kinetics and measurable plasma or urinary levels position them as implementable biomarkers and targets for selective augmentation.

Figure 3.

Exercise-induced metabolites mediate improvements in metabolic health. Exercise stimulates lactate production and release from skeletal muscle. Circulating lactate is subsequently taken up by CNDP2-expressing epithelial and immune cells, where it is conjugated with phenylalanine to generate Lac-Phe. Lac-Phe suppresses appetite and improves metabolic profiles. In parallel, a PGC-1α-dependent pathway in skeletal muscle elevates L-BAIBA, which acts on white adipose tissue and liver to enhance browning and fatty acid oxidation, reduce fat accumulation, and improve insulin sensitivity. Exercise also stimulates brown adipose tissue to release 12,13-diHOME, which in turn improves insulin sensitivity, lipid profiles, and cardiac function. In the kidney, CHDH converts choline to betaine during exercise. Betaine attenuates TBK1 signaling, limits cellular senescence and inflammation, promotes hepatic FGF21 secretion, and helps maintain glucose and lipid homeostasis. AgRP: Agouti-related peptide; CHDH: Choline dehydrogenase; CNDP2: Carnosine dipeptidase 2; FGF21: Fibroblast growth factor 21; KATP: ATP-sensitive potassium; Lac-Phe: N-lactoyl-phenylalanine; L-BAIBA: L-β-aminoisobutyric acid; PGC-1α: Peroxisome proliferator-activated receptor γ coactivator 1-α; PVN: Paraventricular nucleus; TBK1: TANK-binding kinase 1; 12,13-diHOME: 12,13-dihydroxy-9Z-octadecenoic acid. Created with BioRender.com.

Concluding Remarks and Future Perspectives

Research on exerkines has facilitated the development of several therapeutic leads for obesity-related metabolic comorbidities [Table 1]. Among them, FGF21 analogs are now in Phase 3 clinical trials for treatment of obesity-related MASLD, particularly metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis.^[141,200] In parallel, emerging clinical evidence supports multitarget and combination strategies, with GLP-1/FGF21 dual agonism and the addition of FGF21 analogues to GLP-1 receptor agonist therapy showing clinically meaningful improvements in hepatic and metabolic outcomes relevant to MASLD and MASH, particularly among individuals with metabolic comorbidities such as T2DM.^[201,202] Drug development targeting GDF15 signaling is also advancing rapidly, with the engineered GDF15 analogs already being entered early-phase trials.^[153–155] Myostatin inhibitors are under clinical evaluation to augment muscle mass and improve insulin sensitivity, mimicking the effects of resistance training.^[91–93] Short-term IL-6 receptor agonism is being explored to reproduce exercise-like IL-6 signaling, with IC7Fc demonstrating insulin-sensitizing and antisteatotic effects in preclinical models.^[48] Recognition of the gut microbiota as a transducer of exercise intervention has stimulated great interest in promoting the use of prebiotics and probiotics as oral exercise mimetics.^[6,172] In addition, betaine, a kidney-derived metabolite, shows promising clinical potential for glucose lowering and for reducing hepatic steatosis.^[191,192] Furthermore, baseline exerkine signatures may also help forecast responsiveness to training and thus assist personalized exercise interventions. Beyond drug development, exerkine biology informs exercise prescription. For instance, HIIT induces transient increases in IL-6 that improve glucose metabolism, suggesting its utility in T2DM.^[8] Resistance training suppresses myostatin and promotes muscle mass, making it particularly relevant for individuals with prediabetes or sarcopenia.^[8]

Table 1.

Overview of preclinical and clinical studies of major exerkines.

Target	Pharmacologic agent	Type of agent	Subject	Dose	Duration	Study participants	Phase	Status	Trials ID
Skeletal muscle-derived exerkines
IL6	IC7Fc	Chimera	DIO mice	–	–	–	–	–	–
Myostatin	Trevogrumab	Monoclonal antibody	Human	Multiple ascending dose	40 weeks	Healthy postmenopausal females and healthy adult males	I	Completed	NCT02943239
	Bimagrumab	Monoclonal antibody	Human	Unknown	13 weeks	Healthy participants	I	Completed	NCT06890611
	Bimagrumab	Monoclonal antibody	Human	10 or 30 mg/kg at week 4, 16, 28, and 40	48 weeks	Overweight or obese individuals	II	Completed	NCT05616013
	Bimagrumab	Monoclonal antibody	Human	10 mg/kg for every 4 weeks	48 weeks	Overweight and obese individuals with T2DM	II	Completed	NCT03005288
	Bimagrumab	Monoclonal antibody	Human	70, 210, or 700 mg monthly	21 weeks	Older individuals with sarcopenia	II	Completed	NCT02333331
	Bimagrumab	Monoclonal antibody	Human	Unknown	24 weeks	Individuals with sarcopenia and mobility limitations	II	Completed	NCT01601600
	Bimagrumab	Monoclonal antibody	Human	Unknown	24 weeks	Individuals with obesity or overweight	II	Active, not recruiting	NCT06643728
	Bimagrumab	Monoclonal antibody	Human	300 mg every week	52 weeks	Individuals with obesity	II	Recruiting	NCT05933499
	Apitegromab	Monoclonal antibody	Human	2 or 20 mg/kg for every 4 weeks	12 months	Individuals with later-onset spinal muscular atrophy	II	Completed	NCT03921528
	Apitegromab	Monoclonal antibody	Human	10 or 20 mg/kg for every 4 weeks	Up to 52 weeks	Individuals with later-onset spinal muscular atrophy	III	Completed	NCT05156320
Adipose and hepatic exerkines
Adiponectin	AdipoRon	Receptor agonist	DIO mice	–	–	–	–	–	–
FGF21	Pegbelfermin	Analogues	Human	10, 20, or 40 mg weekly	48 weeks	Individuals with MASH and compensated liver cirrhosis	II	Completed	NCT03486912
	Pegbelfermin	Analogues	Human	10 mg daily or 20 mg weekly	16 weeks	Individuals with MASH	II	Completed	NCT02413372
	Pegbelfermin	Analogues	Human	1, 5, or 20 mg daily or 20 mg weekly	12 weeks	Obese individuals with T2DM	II	Completed	NCT02097277
	Pegbelfermin	Analogues	Human	10, 20, or 40 mg weekly	48 weeks	Individuals with MASH and stage 3 liver cirrhosis	II	Completed	NCT03486899
	Pegozafermin	Analogues	Human	20 or 30 mg weekly	26 weeks	Individuals with severe hypertriglyceridemia	III	Active, not recruiting	NCT05852431
	Pegozafermin	Analogues	Human	Unknown	52 weeks	Individuals with MASH and fibrosis	III	Recruiting	NCT06318169
	Pegozafermin	Analogues	Human	9, 18, 27 mg weekly or 36 mg every two weeks	8 weeks	Individuals with severe hypertriglyceridemia	II	Completed	NCT04541186
	Pegozafermin	Analogues	Human	Unknown	Up to 5 years	Individuals with compensated cirrhosis due to MASH	III	Recruiting	NCT06419374
	Pegozafermin	Analogues	Human	3, 9, 18, or 27 mg weekly, 18 or 36 mg every 2 weeks; 27 mg weekly	12 weeks; 20 weeks	Individuals with MASH and MAFLD at high risk of MASH; individuals with biopsy-proven MASH	I–II	Completed	NCT04048135
	Efruxifermin	Analogues	Human	28, 50, or 70 mg weekly	16 weeks	Individuals with MASH	II	Completed	NCT03976401
	Efruxifermin	Analogues	Human	50 mg weekly	96 weeks	Individuals with compensated liver cirrhosis due to MASH	III	Recruiting	NCT06528314
	Efruxifermin	Analogues	Human	28 or 50 mg weekly	24 weeks	Individuals with non-cirrhotic MASH	II	Completed	NCT04767529
	Efruxifermin	Analogues	Human	28 or 50 mg weekly	Up to 96 weeks	Individuals with MASH and stage 4 liver cirrhosis	II	Active, not recruiting	NCT05039450
	Efruxifermin	Analogues	Human	28 or 50 mg weekly	52 weeks	Individuals with MASH and fibrosis	III	Recruiting	NCT06215716
	Efruxifermin	Analogues	Human	50 mg weekly	52 weeks	Individuals with MASH and MASLD	III	Active, not recruiting	NCT06161571
GDF15	MBL949	Analogues	Human	Multiple ascending dose	14 weeks	Obese participants with or without T2DM	II	Terminated	NCT05199090
	LY3463251	Analogues	Human	Multiple ascending dose	10 weeks, 12 weeks	Healthy and overweight healthy subjects	II	Terminated	NCT03764774
	NNC0247-0829	Analogues	Human	Unknown	11–23 weeks	Individuals with overweight or obesity	I	Completed	NCT04010786
Probiotic
FB0054	Probiotic	Human	7.5 or 15 billion CFU daily	4 weeks	Healthy participants	–	Completed	NCT06141343
	FB004	Probiotic	Human	1 x 109 CFU daily	2 weeks	Healthy participants	–	Completed	NCT05816291
Natural compound
–	Betaine	Chemical	Human	4 g daily for 4 weeks and 4 or 8 g daily for 8 weeks	12 weeks	Individuals with non-cirrhotic MASLD and elevated ALT	–	Recruiting	NCT03073343
	Betaine	Chemical	Human	3 g daily	14 weeks	Individuals with overweight or obesity	–	Recruiting	NCT06758856
	Betaine	Chemical	Human	3300 mg twice daily for 10 days, then 4950 mg twice daily	12 weeks	Obese participants with prediabetes	II	Completed	NCT01950039
	Betaine	Chemical	Human	20 mg daily	1 year	Individuals with MASH	II	Completed	NCT00586911
	Betaine	Chemical	Human	3888 mg daily	1 year	Individuals with autoimmune gastritis	–	Recruiting	NCT06881511
	Betaine	Chemical	Human	50 mg/kg	12 weeks	Individuals with refractory syringomyelia	II	Recruiting	NCT06308367
	Betaine	Chemical	Human	3 g daily	8 weeks	Overweight or obese pre-menopausal females	–	Completed	NCT06344377
	Betaine	Chemical	Human	12 or 20 g daily	2 months	Individuals with type 1 primary hyperoxaluria	II	Completed	NCT00283387
Combination therapies or multi-target agonists
Pro-myostatin and GLP-1/GIP	Apitegromab and Tirzepatide	Monoclonal antibody and analogues	Human	Unknown	24 weeks	Individuals with overweight or obesity	II	Completed	NCT06445075
Myostatin, activin A, and GLP-1	Trevogrumab, Garetosmab, and Semaglutide	Monoclonal antibody and analogues	Human	Unknown	Up to 52 weeks	Healthy participants and individuals with obesity	II	Active, not recruiting	NCT06299098
FGF21 and GLP-1	Efruxifermin and one of Semaglutide, Liraglutide, and Dulaglutide	Analogues or fusion protein	Human	50 mg Efruxifermin weekly	12 weeks	Individuals with T2DM and compensated cirrhosis due to MASH	II	Active, not recruiting	NCT05039450
FGF21/GLP-1	HEC88473	Fusion protein	Human	Multiple ascending dose	Single injection or 5 weeks	Healthy participants, obese individuals, and individuals with T2DM	I	Completed	NCT05943886

–: Not available. ALT: Alanine aminotransferase; GLP-1: Glucagon-like peptide-1; FGF21: Fibroblast growth factor 21; GDF15: Growth differentiation factor 15; GIP: Glucose-dependent insulinotropic polypeptide; IL6: Interleukin 6; MASH: Metabolic dysfunction-associated steatohepatitis; MASLD: Metabolic dysfunction-associated steatotic liver disease; T2DM: Type 2 diabetes mellitus.

Despite the significant advances, several challenges remain in translating exerkine biology into clinical implementation. First, the exerkine network and its reciprocal interactions are complex and require systematic elucidation. Thus far, the majority of functional and mechanistic studies have been focusing on an individual exerkine. However, exerkines do not work alone, but coordinate functionally to mediate the metabolic adaptation to exercise. Single-target interventions rarely recapitulate the full effect of exercise.^[13] In this perspective, future work should be focused on elucidating the functional crosstalk among the key exerkines (such as IL-6, FGF21, adiponectin, and GDF15) and how their intracellular signaling pathways converge to coordinate metabolic adaptation to exercise. Second, important knowledge gaps persist regarding how different exercise modalities and intensities modulate exerkine profiles. Most studies only examine a single modality, whereas there is scarce published information available to compare the effects of different exercise modalities/intensities on exerkine production and activities. Third, exercise resistance remains a major barrier. Several exerkines change in opposite directions in exercise responders and nonresponders. Further defining these divergent patterns of exerkines may help to design personalized training strategies for improving the metabolic outcomes of exercise intervention.^[6,172]

Last, the impacts of sex, age, and ethnic background on exerkine production, kinetics, and functionality represent another unexplored research gap. The majority of data on exerkines has been generated in males without strict stratification of age and ethnicity, which limits the generalizability. In this connection, ongoing MoTrPAC project that compares endurance and resistance exercise, assesses the effects of varying exercise intensities, and examine sex-specific changes is expected to address how these factors influence the dynamic changes of exerkine regulatory network.^[13,14]

In summary, the development of exerkine-based mimetics is a rapidly advancing field with clear therapeutic potential, but it faces substantial obstacles. Exercise induces a vast and orchestrated release of numerous exerkines. A drug that mimics the effect of a single beneficial exerkine can only harness a small subset of the benefits of exercise, and is unlikely to recapture this complex, multitargeted symphony. Looking ahead, the exploration of artificial intelligence (AI) and advanced bioinformatics to analyze the complex, dynamic networks of exerkine biology represents an exciting opportunity for discovery and development of multitargeted exerkine mimetics. Well-designed clinical trials, assisted by AI, are also critical to validate the efficacy and safety of exerkine mimetics. Such therapeutic agents are envisioned to be extremely valuable for the patients who are unable to exercise due to disability, frailty, and other chronic disorders. In addition to exerkine-based therapeutics, the development and clinical validation of exerkine-based algorithm with AI represent another exciting field which can help to predict the individual responses to exercise and to guide the strategies for precision exercise medicine.

Funding

This work was supported by grants from the National Key Research and Development Program of China (No. 2022YFA0806102), the Areas of Excellence Scheme of the Research Grants Council of Hong Kong (No. AoE/M-707/18), the National Natural Science Foundation of China (Nos. 82401011 and 82201449), and Shenzhen Natural Science Foundation in Basic Research Fund (No. JCYJ20250604180820027).

Conflicts of interest

None.