Can Myokines Serve as Supporters of Muscle–Brain Connectivity in Obesity and Type 2 Diabetes? Potential of Exercise and Nutrition Interventions

BDNF, a member of the neurotrophin family, is indispensable for neuronal survival, synaptic plasticity, and cognitive function [33]. While its primary source is the CNS, skeletal muscle has emerged as an additional site of BDNF production, particularly under contractile or metabolic stimuli [33]. Muscle-derived BDNF promotes mitochondrial biogenesis, enhances fatty acid oxidation, and regulates myoblast differentiation through activation of AMPK signaling [34].

Beyond these metabolic functions, BDNF has been explored as a potential contributor to communication between muscle and brain [35]. Circulating BDNF may cross the BBB under certain physiological conditions and may influence hippocampal neurogenesis and plasticity [33]. Although the contribution of skeletal muscle to circulating BDNF remains uncertain, increased muscular expression of BDNF during exercise could potentially enhance this signaling pathway, supporting the concept of a muscle–brain connection.

In metabolic disorders, BDNF expression exhibits vulnerability to chronic stress and disease progression [36]. Reductions in muscle- and brain-derived BDNF have been consistently observed in both experimental models and clinical studies, with lower levels correlating with insulin resistance, cognitive decline, and sarcopenia [33,36,37,38]. Our previous findings demonstrated that diabetic mice displayed markedly reduced BDNF in skeletal muscle, plasma, and hippocampal tissue, indicating systemic impairment across the muscle–brain axis [59]. Chronic metabolic stress and neuroinflammation may also impair BDNF–TrkB signaling in the CNS, contributing to reduced responsiveness despite the presence of circulating BDNF [58]. Such alterations could attenuate downstream pathways such as CREB activation and thereby weaken neuroplastic adaptations [58,60].

From a translational perspective, these features make BDNF a compelling biomarker for monitoring metabolic–neurocognitive deterioration, as well as a therapeutic target. Interventions such as physical activity and nutritional strategies that support BDNF signaling are under investigation, but further mechanistic and longitudinal studies are required to establish their translational value in OB and T2DM.

Irisin, a cleaved fragment of fibronectin type III domain-containing protein 5 (FNDC5), has been identified as a key exercise-induced myokine with pleiotropic metabolic and neurocognitive functions [61]. In skeletal muscle, irisin facilitates mitochondrial biogenesis, promotes fatty acid oxidation, and drives the browning of white adipose tissue, thereby enhancing systemic energy expenditure and glucose homeostasis [39,40]. Through activation of PGC-1α-dependent pathways, irisin also regulates myogenic differentiation and preserves muscle metabolic flexibility [40].

Beyond these peripheral actions, irisin exerts significant effects on the CNS. Importantly, irisin crosses the BBB and induces hippocampal BDNF expression, leading to enhanced synaptic plasticity, neurogenesis, and memory performance [41,62]. This capacity to couple muscle activity with higher-order cognitive function positions irisin as a critical effector of the muscle–brain axis [8].

Clinical and experimental evidence indicates that circulating irisin levels are reduced under metabolic stress, including OB and T2DM, with declines correlating with insulin resistance, sarcopenia, and cognitive dysfunction [62,63]. Conversely, exercise and certain nutritional interventions restore irisin expression, linking its modulation to both metabolic resilience and neuroprotection [41,64,65]. However, conflicting clinical findings have also been reported [66]. For example, higher circulating irisin levels have been associated with early cognitive deficits in patients with poorly controlled T2DM, suggesting that elevated irisin may, in some cases, reflect compensatory responses rather than protective activity [66]. Such heterogeneity underscores the complexity of interpreting circulating irisin as a biomarker.

From a translational perspective, irisin represents both a biomarker for metabolic-neurocognitive deterioration and a therapeutic target, where lifestyle or dietary strategies aimed at sustaining irisin secretion may yield dual benefits in the prevention and management of OB and T2DM. Further longitudinal studies are required to clarify whether changes in circulating irisin directly translate into cognitive benefits in humans.

FGF21 is a stress-responsive hormone primarily secreted by the liver but also expressed in skeletal muscle, where it functions as a metabolic regulator and myokine [67,68]. Within muscle, FGF21 enhances glucose uptake, fatty acid oxidation, and mitochondrial biogenesis, while simultaneously mitigating oxidative stress through AMPK/SIRT1 activation [42]. Importantly, in human skeletal muscle, FGF21 has been shown to directly promote glucose uptake and improve insulin sensitivity, supporting its physiological relevance in metabolic homeostasis [43]. These effects contribute to the preservation of metabolic homeostasis under nutrient overload or stress conditions.

In addition to its peripheral roles, FGF21 penetrates the BBB and modulates neuronal plasticity by activating IGF-1/CREB signaling, which subsequently induces BDNF expression [44]. This crosstalk highlights FGF21 as a molecular integrator of muscle–brain communication, linking energy metabolism with neurocognitive function [4].

Under metabolic disorders, FGF21 expression is paradoxically elevated in circulation but often accompanied by FGF21 resistance, characterized by impaired signaling in target tissues [45,46]. This resistance state correlates with insulin resistance, hepatic steatosis, and cognitive impairment. Previous studies indicate that FGF21 expression and circulating levels exhibit stage-dependent changes during metabolic disease progression [69,70,71]. In early or compensatory stages of OB and insulin resistance, circulating FGF21 was upregulated as an adaptive response to metabolic stress or lipid overload [69,70]. However, in more advanced stages such as overt T2DM, this increase is often accompanied by impaired downstream signaling referred to as FGF21 resistance resulting in diminished metabolic and neuroprotective efficacy [71]. These findings suggest that the physiological impact of FGF21 may vary according to disease stage, reflecting a shift from compensatory adaptation to functional resistance.

Nonetheless, pharmacological FGF21 analogs and exercise-based interventions have been shown to restore its metabolic and neuroprotective functions [44,67,72,73]. Collectively, these findings underscore the dual potential of FGF21 as a biomarker of metabolic stress and a therapeutic target, offering opportunities to simultaneously improve systemic metabolism and cognitive health in OB and T2DM.

CTSB is a lysosomal cysteine protease traditionally recognized for intracellular protein turnover, but more recently identified as an exercise-inducible myokine with implications for both muscle homeostasis and brain function [74,75]. In skeletal muscle, CTSB contributes to mitochondrial quality control, autophagy, and inflammatory regulation, particularly under conditions of metabolic overload [76]. Its upregulation with exercise supports muscle remodeling and resilience against catabolic stress [76].

Strikingly, CTSB is capable of crossing the BBB, where it enhances hippocampal neurogenesis and synaptic plasticity, partly through the induction of BDNF-related signaling pathways [4]. Experimental studies have demonstrated that increased CTSB activity is associated with improved memory and learning performance, linking its exercise-induced secretion to neurocognitive benefits [47].

In metabolic disease, alterations in CTSB expression or activity have been reported in muscle and brain, although the direction and magnitude of these changes remain inconsistent across studies. Such dysregulation has been linked with impaired muscle function, insulin resistance, and cognitive vulnerability [74,75]. Interventions such as aerobic exercise and dietary modulation have been shown to increase CTSB levels, and these responses may contribute to the maintenance of both muscle function and cognitive health in metabolic disease. Nevertheless, additional mechanistic and longitudinal human studies are warranted to determine whether CTSB could serve as a clinically informative biomarker or therapeutic target in OB and T2DM.

IL-6 was the first myokine to be identified and is known for its diverse biological activities, displaying both pro- and anti-inflammatory properties depending on the physiological context [77]. Under physiological conditions, it is predominantly secreted by contracting skeletal muscle during exercise, where it promotes glucose uptake via GLUT4, enhances fatty acid oxidation, and stimulates myogenic differentiation through PI3K/AMPK activation [48,49]. Importantly, muscle-derived IL-6 can cross the BBB, where it interacts with neurons and glial cells to facilitate synaptic plasticity, BDNF-related neurotrophic signaling, and cognitive enhancement [4]. These transient elevations are thus considered adaptive and beneficial responses to metabolic stress.

In contrast, during chronic OB and progression to T2DM, IL-6 expression becomes sustained and increasingly derived from adipose tissue, liver (Kupffer cells), and immune cells [50,61]. This persistent elevation shifts IL-6 toward a pro-inflammatory phenotype, driving low-grade systemic inflammation, insulin resistance, and skeletal muscle catabolism [77,78]. Mechanistically, chronic IL-6 suppresses insulin signaling by downregulating GLUT4 and IRS-1, while impairing neuronal excitability and synaptic integrity, thereby contributing to muscle wasting and neurodegenerative processes [50].

Taken together, IL-6 exemplifies a dual-function myokine: acutely elevated and muscle-derived IL-6 supports metabolic and neurocognitive health, whereas chronically elevated and systemically derived IL-6 fosters metabolic deterioration and neuroinflammation. This dichotomy highlights the importance of source- and context-dependent IL-6 signaling when considering therapeutic targeting strategies.

Myostatin, a member of the TGF-β superfamily, is a well-established negative regulator of skeletal muscle growth and regeneration [54]. Under physiological conditions, basal levels of myostatin play a critical role in maintaining muscle homeostasis by constraining excessive hypertrophy and ensuring balanced turnover of muscle fibers [51]. This regulatory role is essential for preserving muscle quality and preventing aberrant energy expenditure.

However, in the context of chronic OB and T2DM, myostatin expression is markedly elevated in skeletal muscle and circulation, where it exerts deleterious effects on metabolic and neurocognitive health [52,53]. Elevated myostatin inhibits Akt/mTOR signaling, suppresses protein synthesis, and promotes ubiquitin–proteasome-mediated protein degradation, thereby accelerating muscle wasting and sarcopenia [51,54]. In addition, myostatin impairs insulin signaling by downregulating IRS-1 and GLUT4 expression, aggravating insulin resistance and glucose intolerance [55]. Beyond skeletal muscle, myostatin has been shown to affect the CNS by reducing neurogenesis and synaptic plasticity, contributing to cognitive decline observed in metabolic disease [79,80].

On the other hand, emerging evidence suggests that the role of myostatin may be more complex and context-dependent. For instance, higher circulating myostatin levels were associated with a lower amyloid burden in older adults, possibly through autophagy-mediated amyloid clearance [81]. Similarly, increased myostatin levels have been observed in physically active or non-frail individuals after exercise, suggesting that transient elevations may reflect adaptive muscle signaling rather than purely catabolic processes [82]. These findings indicate that myostatin may exert different effects depending on metabolic and neurodegenerative context, warranting further investigation into its dual roles in the muscle–brain axis.

Thus, basal myostatin appears to support homeostatic regulation, whereas chronically elevated myostatin in metabolic stress conditions may contribute to muscle atrophy and metabolic dysfunction [52,53,54,55,79,80,81,82]. Understanding this context-dependent regulation may help identify optimal strategies for targeting myostatin to preserve muscle mass and cognitive function in metabolic disease.

Taken together, currently available evidence suggests that myokines may exert context-dependent effects during metabolic disease progression. Some myokines show biphasic actions—promoting metabolic and neurocognitive benefits under physiological or transient stress, but leading to pathological outcomes when chronically elevated or secreted from extra-muscular tissues [59,62,67,74]. In contrast, other myokines act predominantly as pathological mediators, contributing to sustained inflammation, insulin resistance, and neurodegeneration irrespective of disease stage of OB and T2DM [50,52].

The dual role of myokines underscores those therapeutic strategies must be tailored to the biological properties of each factor, including its cellular origin, temporal pattern of secretion, and the stage of disease progression. Such precision is essential for harnessing their protective potential while minimizing the detrimental consequences of myokine dysregulation in OB and T2DM.

While the current review highlights myokines with proposed direct effects on the CNS, various other muscle-derived factors may indirectly influence brain function. Myokines including apelin, myonectin, meteorin-like, and SPARC may modulate systemic metabolism, appetite control, and sleep regulation, potentially contributing to muscle–brain cross-talk through metabolic and endocrine pathways [83]. However, their contribution to neural outcomes remains less clearly defined, and further research is needed to determine whether these myokines exert meaningful effects on the muscle–brain axis in metabolic diseases such as OB and T2DM.

Vitamin A, particularly in its bioactive form all-trans retinoic acid (ATRA), plays a regulatory role in cellular differentiation, lipid metabolism, and mitochondrial function [79]. In the context of OB and metabolic dysregulation, ATRA has been shown to modulate adipogenesis and improve systemic energy balance [99,100]. Notably, ATRA enhances the expression of irisin in myoblasts, suggesting a potential link to muscle-derived endocrine activity. However, further in vivo and clinical studies are required to determine its relevance to sarcopenia [100].

On the other hand, vitamin A also exhibits neuroprotective effects by supporting synaptic plasticity and attenuating neuroinflammatory processes [101]. Animal and human studies indicate that vitamin A supplementation may improve memory performance and prevent OB-related cognitive decline [101].

These findings collectively highlight its potential to alleviate metabolic complications through modulation of the muscle–brain axis.

Vitamin D deficiency is commonly observed in individuals with OB and T2DM, and has been associated with insulin resistance, systemic inflammation, and impaired muscle function [14,102]. Beyond its classical role in calcium homeostasis, vitamin D is now recognized as a key modulator of skeletal muscle health and inter-organ communication [103].

Experimental studies have shown that vitamin D supplementation attenuates muscle atrophy by downregulating proteolytic markers such as atrogin-1 and MuRF1, thereby preserving muscle mass and strength in metabolic disease models [15]. Importantly, vitamin D also modulates the expression of myokines, which are critical mediators of muscle–brain crosstalk.

In T2DM mouse models, vitamin D supplementation has been shown to increase the expression of irisin, a myokine known to promote mitochondrial function, fatty acid oxidation, and BDNF production in the brain [65]. Consistently, clinical trials have demonstrated that six months of vitamin D supplementation elevates circulating irisin levels in humans [104], suggesting a conserved role for vitamin D in enhancing myokine-mediated signaling.

In the CNS, vitamin D exerts neuroprotective effects by supporting glial cell function, maintaining synaptic integrity, and enhancing hippocampal signaling [105]. Vitamin D insufficiency has been linked to increased risk of cognitive impairment in both aging populations and individuals with metabolic disorders [16]. Moreover, higher concentrations of vitamin D in brain tissue have been correlated with better cognitive performance in older adults [106].

Collectively, current evidence suggests that vitamin D supplementation may help attenuate sarcopenia and cognitive decline associated with metabolic diseases. These effects are proposed to be partly mediated through modulation of myokine expression, although direct causal relationships remain to be established.

PUFAs, particularly omega-3 fatty acids, have been reported to exert anti-inflammatory effects and are associated with improvements in various metabolic parameters [107]. Numerous studies have demonstrated the beneficial impact of PUFA intake on metabolic disorders, including enhanced insulin sensitivity, reduced systemic inflammation, and improved lipid profiles [11,108].

In particular, PUFAs influence the expression of muscle-derived signaling molecules, such as irisin and FGF21 [64]. In a previous study, supplementation with 1250 mg of PUFAs three times daily significantly increased serum irisin levels in patients with T2DM [64]. Furthermore, dietary intake of omega-3 (n-3) PUFAs has been positively associated with serum BDNF concentrations in adolescents, suggesting a potential link between PUFA intake and neurotrophic support in the context of psychiatric and metabolic disorders.

These findings imply that PUFAs may influence the skeletal muscle–brain axis indirectly through modulation of key myokines and neurotrophic factors, which could have potential implications for the management of metabolic diseases.

Adequate protein intake is fundamental for maintaining skeletal muscle mass and function, particularly under metabolic stress conditions such as OB and T2DM [109]. Proteins rich in essential amino acids, particularly branched-chain amino acids (BCAAs), activate the mTOR signaling pathway and stimulate muscle protein synthesis [110]. In addition to supporting muscle anabolism, dietary proteins and their bioactive peptides have emerged as important modulators of the muscle–brain endocrine axis, with potential roles in regulating both metabolic and cognitive health [111].

Dietary protein not only enhances muscle protein synthesis but also facilitates the release of specific myokines such as irisin, BDNF, CTSB, and IL-6, which are proposed to mediate peripheral-to-central signaling along the muscle–brain axis [112,113]. These myokines influence key aspects of brain function, such as mood regulation, hippocampal neuroplasticity, and central energy homeostasis, all of which are frequently impaired in the context of metabolic disease [111,112,113].

Beyond total protein intake, specific amino acids have been explored as modulators of metabolic and neurocognitive health. BCAAs, particularly leucine, activate mTOR signaling to support muscle maintenance and may enhance exercise-induced secretion of beneficial myokines such as irisin and IL-6, linking them to improved metabolic capacity [110,114]. Notably, however, metabolic context appears to influence their physiological effects, as chronically elevated BCAAs are associated with impaired mitochondrial metabolism and insulin resistance in OB and T2DM [115].

Beyond BCAAs, additional amino acids with bioactive neurometabolic functions have gained attention. Taurine, a sulfur-containing amino acid, supports muscle integrity by reducing oxidative and inflammatory stress and modulating catabolic myokines such as myostatin [116,117]. These regulatory actions suggest a potential contribution to inter-organ signaling relevant to muscle–brain communication.

Creatine enhances phosphocreatine-dependent ATP regeneration, improves insulin sensitivity, and reduces myostatin signaling [118]. Notably, creatine has been shown to augment exercise-induced increases in BDNF and neurocognitive performance, indicating a potential role in enhancing muscle-derived neurotrophic pathways [119].

Similarly, β-alanine supplementation increases intramuscular carnosine availability, enhancing buffering capacity during exercise and supporting metabolic resilience [120]. Carnosine has also been implicated in neuronal protection and oxidative stress regulation, offering a complementary mechanism that may intersect with muscle-derived endocrine signaling [121].

Taken together, the amino acid composition of dietary protein could influence muscle metabolism and systemic adaptations in a composition-dependent manner, potentially acting through myokine-mediated pathways that affect metabolic and neural health. A more nuanced understanding of these nutrient-specific effects could support precision nutrition strategies tailored to individuals with OB and T2DM.

Polyphenols, including resveratrol and curcumin, are bioactive compounds found in various plant-based foods and have been extensively studied for their potent anti-inflammatory and antioxidant properties [122]. They activate cellular signaling pathways related to energy homeostasis such as AMPK/SIRT1 pathway, leading to the regulation of myokine secretion that mediates muscle–brain crosstalk [122,123,124].

Resveratrol, a polyphenol primarily found in red wine, grapes, and certain berries, has attracted considerable interest for its potential therapeutic effects in metabolic disorders due to its anti-inflammatory and antioxidative properties [125,126]. It has been shown to modulate the expression of myokines such as IL-6 and BDNF [125]. Specifically, resveratrol decreases IL-6 secretion, potentially enhancing muscle regeneration and improving insulin sensitivity in various in vitro and in vivo studies [127]. Resveratrol also crosses the BBB, where it can influence neuroplasticity and cognitive function [128]. By upregulating neurotrophic factors such as BDNF, resveratrol supports neuronal survival and offers neuroprotective effects, which may contribute to the prevention of neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases [129].

Curcumin is the active compound found in turmeric and has long been recognized for its potent anti-inflammatory, antioxidant, and neuroprotective properties [130,131]. It is particularly effective in modulating inflammatory responses and supporting the health of both skeletal muscle and the brain [132,133]. Curcumin has been shown to influence the release of myokines such as irisin, thereby contributing to improved muscle metabolism and regeneration [134]. Additionally, curcumin promotes the expression of neurotrophic factors, including BDNF, and attenuates neuroinflammation, which may enhance cognitive performance and provide protection against neurodegenerative conditions [135,136]. Its ability to modulate the gut–brain axis further reinforces its role in preserving brain function, particularly under metabolic stress [137].

Collectively, polyphenols such as resveratrol and curcumin exert antioxidant and anti-inflammatory effects that counteract the pathophysiological mechanisms underlying sarcopenia and cognitive impairment. In addition to their direct benefits on muscle metabolism and neurotrophic signaling, these compounds may potentially enhance the release of neuroprotective myokines, thereby strengthening muscle–brain crosstalk and amplifying their therapeutic potential for metabolic and cognitive health in the context of obesity and T2DM. In summary, both exercise and dietary interventions have been suggested as potential strategies to modulate myokine signaling within the muscle–brain axis in metabolic disease. While preliminary findings indicate possible benefits, the current evidence remains insufficient to demonstrate a direct causal relationship, particularly in humans. Therefore, further mechanistic and well-controlled clinical studies are warranted to determine whether such interventions can effectively preserve both metabolic and cognitive health. Aerobic and resistance training stimulate the release of neurotrophic and metabolically beneficial myokines, thereby counteracting sarcopenia and cognitive decline. Complementarily, specific nutritional interventions including vitamins, PUFAs, proteins, and polyphenols, further augment myokine secretion and support inter-organ communication. Given the bidirectional communication between skeletal muscle and the brain, lifestyle interventions including diet and exercise that attenuate diabetic muscle atrophy may have the potential to indirectly support neurocognitive resilience by possibly improving myokine signaling and reduced systemic inflammation. Importantly, the efficacy of these approaches is highly dependent on age and disease stage, underscoring the necessity of tailored interventions. When implemented in combination, exercise and nutrition offer synergistic benefits that reinforce muscle and brain health, highlighting their potential as integrated therapeutic strategies for mitigating the metabolic and neurocognitive complications of OB and T2DM.

Although several studies suggest that nutritional modulation can influence myokine secretion and related pathways, evidence directly linking these changes to improvements in muscle–brain communication remains limited. Further mechanistic and clinical studies are needed to clarify their translational relevance in metabolic disease.