Exercise-Induced Muscle-Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging

Abstract

Regular physical activity induces a dynamic crosstalk between skeletal muscle and adipose tissue, modulating the key molecular pathways that underlie metabolic flexibility, mitochondrial function, and inflammation. This review highlights the role of myokines and adipokines-particularly IL-6, irisin, leptin, and adiponectin-in orchestrating muscle-adipose tissue communication during exercise. Exercise stimulates AMPK, PGC-1α, and SIRT1 signaling, promoting mitochondrial biogenesis, fatty acid oxidation, and autophagy, while also regulating muscle hypertrophy through the PI3K/Akt/mTOR and Wnt/β-catenin pathways. Simultaneously, adipose-derived factors like leptin and adiponectin modulate skeletal muscle metabolism via JAK/STAT3 and AdipoR1-mediated AMPK activation. Additionally, emerging exercise mimetics such as the mitochondrial-derived peptide MOTS-c and myostatin inhibitors are highlighted for their roles in increasing muscle mass, the browning of white adipose tissue, and improving systemic metabolic function. The review also addresses the role of anti-inflammatory compounds, including omega-3 polyunsaturated fatty acids and low-dose aspirin, in mitigating NF-κB and IL-6 signaling to protect mitochondrial health. The resulting metabolic flexibility, defined as the ability to efficiently switch between lipid and glucose oxidation, is enhanced through repeated exercise, counteracting age- and disease-related mitochondrial and functional decline. Together, these adaptations demonstrate the importance of inter-tissue signaling in maintaining energy homeostasis and preventing sarcopenia, obesity, and insulin resistance. Finally, here we propose a stratified treatment algorithm based on common age-related comorbidities, offering a framework for precision-based interventions that may offer a promising strategy to preserve metabolic plasticity and delay the age-associated decline in cardiometabolic health.

Keywords: IL-6; adipokines; adiponectin; irisin; leptin; metabolic flexibility; mitochondrial biogenesis; myokines; skeletal muscle–adipose tissue crosstalk.

Figure 1

Metabolic effect of the myokine IL-6 released during exercise. Muscle activity leads to lactic acid formation in skeletal muscle because of glycolysis, along with the depletion of intramuscular glycogen stores. Owing to the intensification of mitochondrial oxidative metabolism, there is an increased production of reactive oxygen species (ROS) and oxidative stress. The red arrows indicate the main promoters of IL-6 release from the muscle during exercise. The release of IL-6 into the circulation promotes the mobilization of fatty acids from adipose tissue by activating enzymes such as hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL), and α-ketoglutarate dehydrogenase (AOX), while simultaneously inhibiting fatty acid synthesis via the inhibition of fatty acid synthase (FAS). In the liver, IL-6 stimulates gluconeogenesis through activation of the gp130/JAK/STAT3 signaling pathway and activation of key gluconeogenic enzymes, including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-P-ase). In skeletal muscle, IL-6-induced activation of AMPK facilitates GLUT-4 translocation and glucose uptake into muscle cells through an insulin-independent mechanism, while also promoting β-oxidation of fatty acids, particularly short-chain fatty acids, for aerobic ATP production. ↑ up arrows mean increase and ↓ down arrows mean decrease. This image was created using BioRender (https://BioRender.com/n4xejkf, accessed on 18 August 2025).

Figure 2

Exercise-induced irisin release promotes browning of white adipose tissue. Physical activity activates PGC-1α expression in skeletal muscle, leading to the cleavage of FNDC5 into the circulating myokine irisin. Irisin acts on white adipocytes to upregulate UCP1, a key thermogenic marker, and initiates mitochondrial biogenesis. This signaling cascade results in the browning of WAT, characterized by increased mitochondrial concentration and enhanced energy dissipation as heat. (PGC-1α—peroxisome proliferator-activated receptor gamma coactivator-1 alpha, FNDC5—fibronectin type III domain-containing protein 5, UCP1—uncoupling protein 1, CPT1—carnitine palmitoyltransferase 1, FAs—fatty acids, ACOX1—acyl-CoA oxidase 1, SIRT1—sirtuin 1, p38 MAPK—p38 mitogen-activated protein kinase, ERK—extracellular signal-regulated kinase, ↑ up arrows mean increase). This image was created using BioRender. (https://BioRender.com/67zf659, accessed on 18 August 2025).

Figure 3

Leptin and adiponectin signaling pathways in skeletal muscle and liver. This schematic illustrates the peripheral actions of the adipokines leptin and adiponectin on skeletal muscle and the liver in the context of physical activity and metabolic regulation. Leptin, which is secreted by adipose tissue, binds to its long-form LepRb in skeletal muscle and the liver. In skeletal muscle, leptin activates the JAK/STAT3, PGC-1α, and AMPK signaling pathways, promoting mitochondrial biogenesis, glucose uptake, and fatty acid oxidation. Leptin, through binding to hepatic LepRb receptors, can inhibit gluconeogenesis and improve lipid metabolism under resting and postprandial conditions. However, during acute physical exercise, this effect is counterbalanced by stress hormones and myokines such as IL-6, which stimulate gluconeogenesis to ensure the necessary ATP supply for active skeletal muscle. Adiponectin, which acts primarily through its receptor AdipoR1 in muscle, stimulates AMPK and PPARα signaling, enhancing glucose uptake, fatty acid oxidation, and mitochondrial function. (LepRb—leptin receptor isoform b, JAK—Janus kinase, STAT3—signal transducer and activator of transcription 3, PGC-1α—peroxisome proliferator-activated receptor gamma coactivator 1-alpha, AMPK—AMP-activated protein kinase, IL-6—interleukin-6, ATPadenosine triphosphate, AdipoR1—adiponectin receptor 1, PPARα—peroxisome proliferator-activated receptor alpha, FAs—fatty acids, ↑ up arrows mean increase). This image was created using BioRender (https://BioRender.com/d3aik7f, accessed on 18 August 2025).

Figure 4

Molecular mechanisms through which exercise regulates skeletal muscle metabolism, mitochondrial quality, and adipose tissue remodeling. Acute exercise increases oxygen consumption and hypoxic stress, leading to elevated ROS and an increased AMP/ATP ratio, which activates AMPK. Activated AMPK phosphorylates and upregulates PGC-1α, promoting mitochondrial quality control via biogenesis, mitophagy, fusion, and fission. PGC-1α also induces FNDC5 expression, resulting in the secretion of irisin, a myokine that stimulates UCP1 expression and browning in white adipose tissue. In parallel, exercise promotes glucose uptake through GLUT4 translocation to the plasma membrane. Chronic exercise activates the PI3K–Akt–mTORC1 pathway by inhibiting the TSC and activating Rheb, thereby supporting protein synthesis and muscle hypertrophy. Resistance training also suppresses C1q-induced Wnt signaling, which otherwise contributes to muscle atrophy and fibrosis. In the absence of Wnt, β-catenin is degraded via a complex that includes GSK-3β, Axin, APC, and CK1α. Wnt activation inactivates this complex, allowing β-catenin to enter the nucleus, bind TCF/LEF, and drive the transcription of genes involved in muscle growth and repair. Together, these pathways contribute to increased metabolic flexibility, improved mitochondrial function, and the prevention of sarcopenia. (AMPK—AMP-activated protein kinase, PGC-1α—Peroxisome proliferator-activated receptor gamma coactivator 1-alpha, FNDC5—Fibronectin type III domain-containing protein 5, UCP1—Uncoupling protein 1, GLUT4—Glucose transporter type 4, ROS—Reactive oxygen species, PI3K—Phosphoinositide 3-kinase, Akt—Protein kinase B, TSC—Tuberous sclerosis complex, Rheb—Ras homolog enriched in brain, mTORC1—Mechanistic target of rapamycin complex 1, BAT—Brown adipose tissue, C1q—Complement component 1q, GSK-3β—Glycogen Synthase Kinase-3 Beta, APC—Adenomatous Polyposis Coli, CK1α—Casein Kinase 1 alpha, TCF—T-cell Factor, LEF—Lymphoid Enhancer-binding Factor, ↑ up arrows mean increase). This image was created using BioRender (https://biorender.com/yhzyxwv, accessed on 18 August 2025).

Figure 5

The coordinated effects of leptin and adiponectin on skeletal muscle metabolism, mitochondrial function, and inflammation. This figure illustrates the regulation of skeletal muscle physiology by leptin and adiponectin. Leptin exerts anabolic and metabolic effects through the activation of the PI3K/Akt pathway via IGF-1, resulting in the suppression of myostatin, increased expression of PCNA and cyclin D, and downregulation of FoxO3a, which reduces atrophy-related gene expression. Leptin also enhances PGC-1α expression and increases glucose uptake by promoting insulin sensitivity and GLUT4 translocation. Additionally, leptin stimulates sympathetic activation (via β-AR), which leads to AMPK activation and downstream inhibition of ACC, reducing malonyl-CoA levels and facilitating fatty acid oxidation. Adiponectin binds to AdipoR1, triggering Ca²⁺ influx and activation of the CaMKK–APPL–LKB1 pathway, which also activates AMPK. This in turn enhances FA transport (FAT/CD36), improves the oxidative stress response, and upregulates PGC-1α, promoting mitochondrial biogenesis and inhibiting FoxO-mediated proteolysis. Through SIRT1, adiponectin further modulates FoxO activity, suppressing proteolytic gene expression. In parallel, adiponectin promotes macrophage polarization toward the anti-inflammatory M2 phenotype, increasing IL-10 secretion and contributing to a protective, anti-inflammatory muscle microenvironment. (IGF-1—Insulin-like growth factor-1, PI3K—Phosphoinositide 3-kinase, Akt—Protein kinase B, PCNA—Proliferating cell nuclear antigen, FoxO—Forkhead box O, AMPK—AMP-activated protein kinase, ACC—Acetyl-CoA carboxylase, FAT/CD36—Fatty acid translocase/Cluster of differentiation 36, PGC-1α—Peroxisome proliferator-activated receptor gamma coactivator-1 alpha, SIRT1—Sirtuin 1, APPL—Adaptor protein containing PH domain, PTB domain and leucine zipper motif, LKB1—Liver kinase B1, CaMKK—Ca²⁺/calmodulin-dependent protein kinase kinase, IL-10—Interleukin-10, M1/M2—Pro-inflammatory (M1) and anti-inflammatory (M2) macrophage phenotypes, β AR—Beta-adrenergic receptor, ↑ up arrows mean increase and ↓ down arrows mean decrease). This image was created using BioRender (https://BioRender.com/r0klswn, accessed on August 2025).

Figure 6

Pharmacological targeting of convergent signaling pathways to enhance metabolic flexibility in aging: an integrated mechanistic model. This figure presents a conceptual framework summarizing how diverse pharmacological agents modulate key molecular pathways to preserve metabolic flexibility, particularly in older individuals with limited physical activity. Metabolic flexibility, the capacity to efficiently switch between glucose and lipid utilization in response to energy demands, is governed by the dynamic interplay of mitochondrial function, nutrient sensing, muscle–fat crosstalk, and low-grade inflammation. The diagram shows how different drug classes exert complementary and sometimes overlapping effects on these regulatory nodes. Metformin and berberine activate AMPK, a central metabolic sensor that enhances glucose uptake, FA oxidation, and mitochondrial biogenesis. PPAR agonists, such as pioglitazone (PPAR-γ) and GW501516 (PPAR-δ, experimental), further promote insulin sensitivity, lipid transport, and oxidative metabolism by upregulating genes involved in mitochondrial function. The SIRT1/PGC-1α axis, activated by compounds such as resveratrol and NAD⁺ precursors (e.g., NR, NMN), promotes mitochondrial health, oxidative phosphorylation, and cellular resilience to stress. Emerging agents that mimic exercise-induced signaling include myostatin inhibitors, which reduce muscle catabolism and enhance myokine secretion (e.g., irisin) leading to white adipose tissue browning and improved thermogenic capacity. Similarly, MOTS-c, a mitochondrial-derived peptide, functions as a potent AMPK activator, improving glucose metabolism and lipid oxidation. In parallel, anti-inflammatory agents such as omega-3 polyunsaturated FAs and low-dose aspirin mitigate chronic low-grade inflammation by attenuating NF-κB and IL-6 signaling, indirectly supporting insulin action and mitochondrial function (AMPK—AMP-activated protein kinase, IL-6—interleukin-6, NF-κB—nuclear factor-κB, MOTS-c—mitochondrial open reading frame of the 12S rRNA type-c, FAs—fatty acids, SIRT1—sirtuin, PGC-1α—peroxisome proliferator-activated receptor gamma coactivator 1-alpha, NAD⁺—nicotinamide adenine dinucleotide, NR—nicotinamide riboside, NMN—nicotinamide mononucleotide, PPAR—peroxisome proliferator-activated receptor, ↑ up arrows mean increase and ↓ down arrows mean decrease).