Physical exercise and irisin: managing obesity and related comorbidities

Abstract

We live in an obesity pandemic characterized by sedentary lifestyles and unhealthy eating habits among more and more people. Therefore, it is crucial to understand the pathophysiology of obesity. A myokine secreted during exercise, irisin, has been the subject of many studies in recent years. It is well-known that physical exercise is one of the key therapeutic pillars in the fight against obesity. Irisin is a polypeptide hormone released during physical activity, and once it enters the bloodstream, it has numerous effects on the human body. This review aimed to highlight the latest studies on irisin, focusing on its structure, the mechanisms behind its release into the bloodstream, its effects on various organs, and, last but not least, how its serum levels change in different pathologies and its therapeutic effects.

Introduction

Obesity is a more significant health problem today than at any known time in history, posing an increasing threat to populations worldwide [1]. The proportion of overweight or obese adults has reached approximately 60%, and one in three children is affected by excess weight, according to the World Health Organization (WHO) European Regional Report on Obesity 2022 [2]. Obesity is characterized by an abnormal accumulation of fat resulting from a disparity between energy intake and consumption [3]. Obesity is also characterized by a reduced grade of inflammation, which appears to be a common core for the onset and progression of various metabolic pathologies such as type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), dementia, osteoporosis (OP), multiple cancers, and so on [3].

“Walking is man’s best medicine”, a statement by Hippocrates shows that even almost two thousand years ago, physical exercise was recognized as playing an important role in maintaining overall health. Nowadays, physical exercise is widely recognized as a primary preventive means for many chronic diseases, but also as a means for their treatment [4].

Muscle tissue plays a role in thermogenesis, respiration, postural support, and locomotion. Several substances called myokines are found to be secreted by muscle tissue during exercise: interleukin (IL)-6, IL-7, IL-15, fibroblast growth factor 21 (FGF21), insulin-like growth factor-binding protein-6 (IGFBP-6), musclin, follistatin-like 1, and irisin [5]. These substances have multiple signaling pathways and exert their action in autocrine, paracrine, and endocrine modes [6].

The data gathered in this review aimed to provide a detailed characterization of irisin and its roles, especially its interaction and metabolic homeostasis. It is well known that physical exercise possesses a wide range of beneficial effects that overlap with the effects of irisin on the whole organism. The following describes irisin, starting with its synthesis, mode of action, effects on different tissues, level in various pathologies, and therapeutic potential.

Irisin biosynthesis

Irisin originates from the cleavage of the fibronectin type III domain-containing protein 5 (FNDC5). FNDC5 (previously named FRCP2 or Pep) was independently discovered in 2002 by two research teams [7, 8]. It is abundantly expressed in skeletal muscle, consists of 209 amino acids and contains several domains: an N-terminal “signal peptide” domain, a fibronectin III domain from which irisin results, a linking peptide domain where the cleavage process takes place, a hydrophobic transmembrane domain and a C-terminal intracytoplasmic carboxyterminal domain [9, 10]. These domains are highlighted in Figure 1. Irisin is released into the bloodstream through extracellular cleavage by disintegrin and A disintegrin and metalloproteinase 10 (ADAM10) [11]. Irisin is a polypeptide hormone with a molecular weight of approximately 12 kDa and a number of 112 amino acids, having been discovered by Boström et al. in 2012. Moreover, a similarity of 100% between human and animal irisin sequences was detected [12].

Figure 1.

Release of irisin. Irisin is a polypeptide hormone that comes from the breakdown of the fibronectin type III domain-containing protein 5 (FNDC5). Created with BioRender.com

Mainly, irisin is secreted by skeletal muscle and adipose tissue, but other organs have a secretory role, such as the liver, lung, heart, tongue, brain, ovaries, and testicles [5]. Because they contain muscle fibers, organs such as skeletal muscles, the heart, blood vessels, and the rectum exhibit high levels of FNDC5 [13]. Figure 2 shows the main tissues releasing irisin, the actions of irisin, and some of its triggers.

Figure 2.

Irisin: site of its synthesis, triggers, and actions. Physical exercise, specific substances, and exposure to cold increase the expression of PGC-1α, a transcriptional gene regulator for FNDC5. Synthesis mainly occurs in skeletal muscle tissue but to a lesser extent in other tissues, such as brown adipose tissue. Cleavage of FNDC5 results in irisin, which has several beneficial pleiotropic effects in skeletal muscle, adipose tissue, liver, heart, bone, nervous tissue, pancreas, and so on. The effects of irisin are very similar to physical exercise, as irisin is a messenger of physical exercise. FNDC5: Fibronectin type III domain-containing protein 5; Glut4: Glucose transporter type 4; PGC-1α: Peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1alpha; WAT: White adipose tissue. Created with BioRender.com

As previously mentioned, the balance between exercise and diet is an important factor that helps maintain body weight at a certain level. These are also among the most studied factors regulating the release of irisin. Therefore, physical exercise increases the upregulation of peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1alpha (PGC-1α), leading to the synthesis of FNDC5 in skeletal muscle and then the entry of irisin into the bloodstream [14]. It appears that FNDC5 synthesis and irisin secretion are negatively related to increased levels of fatty acids, including palmitic acid and glucose [13, 15, 16]. Moreover, a Mediterranean diet is associated with increased irisin levels, and several polyphenols enhance irisin production, with resveratrol being the most extensively studied [17]. Additionally, certain dietary supplements such as ursolic acid [18], as well as several drugs including Simvastatin [19], Fenofibrate [20], Metformin [21], Sitagliptin [22], Retinoic Acid [23], and Follistatin [24] have been shown to increase irisin levels. Among other factors studied are cytokines with a proinflammatory role, such as IL-1β and tumor necrosis factor-beta (TNF-β), which reduce FNDC5 synthesis, as well as oxidative stress [13, 14]. Irisin inhibits the secretion of myostatin [25], a protein secreted by muscle that inhibits muscle growth.

Irisin mechanism of action

The name irisin comes from the Egyptian goddess Isis, the messenger of good news. This name is very close to irisin’s role in the body: a chemical messenger that conveys the beneficial effects of physical exercise throughout the human body [26].

From the first publications concerning irisin, a great step was the discovery of the irisin mechanism of action and its receptors [10]. In 2018, Kim et al. showed that the effects of irisin on adipose and bone tissue are mediated by αv/β5 integrin receptors [27]. Although αv/β5 integrins are receptors for irisin in some tissues, there is also the possibility of other receptors from the integrin family or not [28]. Interaction between irisin and αv integrin receptors triggers a cascade of events that include phosphorylation of focal adhesion kinase (FAK), protein kinase B [29], and cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) [10], etc. These events, along with many others, are summarized in Figure 3.

Figure 3.

Irisin signaling pathways and their effects. Irisin has numerous beneficial effects such as induction of browning, osteocyte proliferation, neuroprotection, neuronal differentiation, increased insulin synthesis, decreased lipogenesis, inhibition of adipogenesis through activation of ERK/MAPK, PI3K/AKT/PKB, AMP/PKA/CREB, AMPK, Wnt signaling pathways. ACC: Acetyl-coenzyme A (CoA) carboxylase; AKT/PKB: Protein kinase B; AMP: Adenosine monophosphate; AMPK: AMP-activated protein kinase; cAMP: Cyclic AMP; CREB: cAMP response element-binding protein; ERK: Extracellular signal-regulated kinase; FAS: Fatty acid synthase; MAPK: Mitogen-activated protein kinase; PI3K: Phosphoinositide 3-kinase; PKA: Protein kinase A; WAT: White adipose tissue; Wnt: Wingless-related integration site. Created with BioRender.com

Irisin acts via the following main intracellular signaling pathways: adenosine monophosphate (AMP)-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), cAMP/protein kinase A (PKA)/CREB, phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) [28, 30, 31]. The primary signaling pathway is the MAPK pathway, which is involved in neuronal differentiation, browning of white adipose tissue (WAT), osteoblast proliferation and differentiation, and glucose uptake by muscle tissue [28, 32]. Using the AMPK and PI3K/AKT pathway, irisin has proliferation, anti-inflammatory, and anti-metastatic effects [28]. Using the cAMP/PKA/CREB pathway has effects in regulating neuronal plasticity and improving memory [28]. By activating Wnt expression, it inhibits adipogenesis [28]. Figure 3 illustrates some of the signaling pathways and their corresponding outcomes.

The tissue-specific localization of irisin receptors, together with the diversity of activated intracellular signaling pathways, underscores the complexity of irisin’s interaction and functional roles across multiple organ systems.

Irisin and beneficial effects

To better illustrate these multiple effects, which target skeletal muscle, adipose tissue, pancreas, bone, nervous tissue, liver, immune system, heart, and kidney, they have been summarized in a synthetic format in Table 1.

Table 1.

Beneficial effects of irisin on the whole body

Tissue	Effect	Refs.
Skeletal muscle	▪ Uptake of glucose ▪ Decreases gluconeogenesis ▪ Decreases glycogenolysis ▪ Increases lipid metabolism ▪ Decreases lipid utilization.	[6, 32, 33, 34]
Adipose tissue	▪ It causes browning of white adipose tissue, accompanied by:</p> ~ Increased energy metabolism ~ Increased glucose utilization ~ Increased lipolysis ~ Decreased lipid accumulation.</p> ▪ Inhibits adipogenesis.	[28, 35, 36]
Liver	▪ Stimulates glycogenogenesis ▪ Inhibits glycogenolysis ▪ Inhibit lipogenogenesis ▪ Prevents triglyceride accumulation ▪ Improves mitochondrial function in hepatocytes.	[6, 34]
Pancreas	▪ Increases insulin synthesis ▪ Increases regeneration of pancreatic β-cells.	[28, 37]
Nervous tissue	▪ Regulates appetite ▪ Induces neuroprotection (via BDNF) ▪ Increases cell survival ▪ Stimulates neuronal differentiation.	[28, 34, 36, 38]
Heart	▪ Lowers blood pressure ▪ Protects against hypertrophy ▪ Protects the heart cell from ischemia ▪ Alleviates atherosclerosis.	[6, 13, 34, 39, 40]
Bone tissue	▪ Decreases the number of osteoclasts ▪ Increases cortical bone mass ▪ Increases the number and differentiation of osteoblasts.	[28, 34, 35, 36, 41, 42, 43]
Kidney	▪ Lowers ROS ▪ Decreases renal fibrosis.	[6, 44, 45, 46]
Immune system	▪ Decreases ROS production ▪ Decreases expression of inflammatory cytokines.	[34, 36, 38]

BDNF: Brain-derived neurotrophic factor; ROS: Reactive oxygen species.

Regarding pharmacokinetics, irisin injected into mice has a half-life of approximately one hour [6, 27]. Thus, the variability in its pharmacological activity and biological measurements can be attributed, at least in part, to its short half-life [47].

Irisin concentration is higher in men than in women at rest and after exercise [48], likely due to the higher muscle mass in men. Irisin also exhibits a circadian secretion rhythm, with the highest levels reached at 9:00 pm and the lowest at 6:00 am [48].

Irisin and skeletal muscle

Skeletal muscle represents 30–40% of body weight, making it the largest tissue in the body [45]. This percentage depends on several determinants, such as diet, level of exercise, presence of chronic diseases, and neoplasia [49]. The health effects of exercise are well known. Recent studies have shown that muscle tissue secretes several myokines with a role in maintaining homeostasis. Atrophy and sarcopenia are the main degenerative pathologies of muscle tissue and are associated with metabolic changes [34]. Reza et al. have highlighted the pro-myogenic role of irisin through hyperexpression of exercise-associated genes in muscle cells, increasing myogenic differentiation [50]. Irisin administration in mice induces hypertrophy, and after muscle injury, it induces muscle regeneration and hypertrophy [50]. Another study examined the proteome profile of mice after long-term administration of injectable irisin and found increased levels of actin, myosin, and tropomyosin compared to the control group [51].

Evidence indicates that exercise induces an increase in FNDC5 expression and serum irisin levels [12, 51]. However, other results show no correlation between irisin levels and physical exercise [52, 53]. This discrepancy can be explained by the existence of different types of exercise with different levels of intensity and duration [54]. Acute exercise immediately increases blood irisin concentration, whereas chronic exercise improves metabolic homeostasis and irisin secretion efficiency [55]. Irisin levels rise three to 60 minutes after exercise and revert to normal six hours later [56, 57]. Resistance exercise and high-intensity exercise are more important for promoting efficient irisin secretion [55].

Irisin, exercise, and exposure to cold

Recent studies have found that exercise combined with cold exposure has a synergistic effect on metabolic homeostasis compared to exercise in a thermoneutral environment [58]. Over time, there has been considerable controversy regarding whether exercising in cold conditions is beneficial for cardiovascular (CV) health. This skepticism stems from the fact that cold exposure increases stress on the CV system. However, it has been shown that exercising in cold environments enhances the body’s tolerance to such stressors. The reason is the activation of the sympathetic nervous system, which has beneficial effects on cellular bioenergetics, antioxidant capacity, and immune response [58].

Irisin and insulin

Another important role of irisin is facilitating glucose uptake in skeletal muscle and improving insulin sensitivity at this level [6]. Irisin enhances the activity of the insulin-induced PI3K/AKT pathway, which leads to increased glucose influx into the muscle cell by promoting translocation of glucose transporter type 4 (Glut4) to the membrane [33]. This is schematized in Figure 4. Irisin improves insulin resistance by activating the AMPK pathway [32].

Figure 4.

Irisin potentiates the insulin signaling pathway. Irisin enhances insulin-induced PI3K/AKT signaling activity, which leads to increased glucose influx into the muscle cell by promoting translocation of GLUT-4 to the membrane. Irisin, like insulin, stimulates glycogenogenesis and initiates gluconeogenesis. AKT: Protein kinase B; FOXO1: Forkhead box protein O1; GLUT-4: Glucose transporter type 4; IRS1: Insulin receptor substrate 1; PEPCK: Phosphoenolpyruvate carboxykinase; PI3K: Phosphoinositide 3-kinase. Created with BioRender.com

By generating a FNDC5 KO murine model, Luo et al. showed that mice deficient in irisin had hyperlipidemia and insulin resistance, reduced high-density lipoprotein (HDL)-cholesterol levels, increased low-density lipoprotein (LDL)-cholesterol levels, and decreased insulin sensitivity [59].

Irisin and obesity

Excessive accumulation of white fat leads to obesity. WAT is the main storage site for fat, but it also plays a fundamental role in metabolism, as has been discovered since 1990 with the discovery of leptin [28].

Studies that have attempted a correlation between obesity and irisin levels have shown that irisin levels show fluctuations in these subjects in both animal and human studies [54]. While some studies have demonstrated downregulation of FNDC5 in both muscle tissue and adipose tissue caused by obesity [60, 61, 62, 63, 64, 65, 66], others have shown no correlation whatsoever [19, 67, 68, 69, 70, 71]. However, a positive correlation between irisin levels and obesity has been documented in the literature [72, 73, 74, 75, 76]. This can be interpreted as a compensatory mechanism in obesity [54]; however, it may also reflect a state of irisin resistance, analogous to the well-known insulin and leptin resistance observed in obesity and T2DM. An alternative explanation could be the increased secretion of irisin by the large mass of WAT [77]. After release, irisin increases energy consumption and improves insulin sensitivity.

Irisin levels correlate positively with leptin levels [78] and negatively with adiponectin levels [79]. A direct irisin and leptin interaction seems unlikely, as leptin administered to humans did not change irisin levels.

Irisin and diabetes

Irisin levels are not only low in patients with type 1 diabetes mellitus and T2DM, but also in gestational diabetes [80, 81, 82, 83, 84]. However, contradictory findings have been reported in T2DM, where elevated levels of irisin have also been identified [85]. These contradictory data in studies result from either the variability of the individuals included, or the enzyme-linked immunosorbent assay (ELISA) kits used for determination. Additional research has focused on the association between irisin levels and insulin resistance. However, these studies have failed to reach a conclusion due to the different types of patients enrolled [54].

Irisin and brown adipose tissue

Brown adipose cells (and the more recently discovered beige fat cells) contain a high number of mitochondria and have the particular ability to convert chemical energy into heat due to the presence of uncoupling protein 1 (UCP1) [86]. Moreover, through the process of browning, white adipose cells can be converted into brown-like adipose cells [87, 88] (Figure 5).

Figure 5.

Irisin and brown adipose tissue. The first discovered effect of irisin is the browning of white adipose tissue. ERK: Extracellular signal-regulated kinase. Created with BioRender.com

Irisin is one of the browning agents that also improves the energy balance, reduces insulin resistance, and improves glucose tolerance [89].

Irisin induces increased UCP1 levels and increased adipocyte energy consumption, decreasing lipid accumulation [25] using the p38/extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathway [10] (Figure 4). A recent study demonstrated that a lack of irisin in mice is accompanied by decreased browning and impaired lipid and carbohydrate metabolism [59]. Thus, irisin may be a new therapeutic target in the fight against obesity.

Irisin and liver

The liver is one of the target organs of irisin. It regulates blood glucose levels through various mechanisms, from the production, absorption, and storage of glucose to the synthesis and degradation of glycogen [38]. Irisin stimulates glycogenogenesis by activating the PI3K/AKT pathway and inhibits gluconeogenesis via the AMPK–phosphoenolpyruvate carboxykinase (PEPCK) pathway [9]. However, not much is known about the irisin receptor in the hepatocyte [9].

The most prevalent liver pathology is non-alcoholic fatty liver disease (NAFLD), induced by increased fat levels in the liver, leading to inflammation and fibrosis [34]. Accumulation of triglycerides in the hepatocyte, either due to lipid metabolism dysfunction or de novo lipogenesis induced by elevated blood glucose levels, is correlated with other metabolic dysfunctions such as insulin resistance, increased blood pressure, and increased transaminase levels [90]. Irisin levels are low among patients with NAFLD [91, 92, 93]. Irisin may improve the status when it comes to NAFLD by decreasing the degree of inflammation [80]. Subcutaneous administration of irisin for two weeks showed decreased intracellular as well as plasma cholesterol content in mice fed a high-fat diet through its action on the AMPK pathway and inhibiting sterol regulatory element-binding protein 2 (SREBP2) [94].

Irisin and nervous tissue

The beneficial effects of exercise on mental health are well established, including reduced risk of dementia, depression, and stress, as well as improved cognitive function [38]. Due to its ability to cross the blood–brain barrier, irisin also exerts its effects inside the brain [29].

Irisin exerts neuroprotective effects by stimulating the synthesis of brain-derived neurotrophic factor (BDNF), a molecule with major roles in neuronal survival, learning, and memory [12, 47].

Alongside the production of BDNF, reducing epidermal growth hormone receptor expression in mice was also thought to ameliorate the postoperative depressive-like behavior [95, 96]. In addition, irisin promotes gene expression linked to the development and maintenance of hippocampal neurons, further supporting its role in cognitive function [12, 47]. Notably, decreased irisin levels have been observed in patients with dementia, suggesting its involvement in disease progression. Irisin contributes to neurogenesis and inhibits the accumulation of amyloid-beta (Aβ), a hallmark of neurodegenerative disorders [97, 98, 99].

In acute events such as cerebral ischemia, irisin plays a crucial neuroprotective role by activating the Akt and ERK1/2 signaling pathways, irisin mediates the beneficial effects of exercise in reducing ischemic brain damage [100]. A study by Li et al. demonstrated that both plasma and muscle irisin levels decrease following cerebral ischemia. Interestingly, higher irisin concentrations were associated with smaller infarct volumes, improved neurological function, and reduced levels of proinflammatory cytokines. Furthermore, the administration of recombinant irisin in stroke-induced mice led to significant neuroprotection, evidenced by reduced infarct size, enhanced functional recovery, and attenuated neuroinflammatory responses [100].

Thus, irisin exerts multiple beneficial effects on the nervous system, in both acute and chronic conditions, and may represent a promising therapeutic target for enhancing cognitive functions [99].

Irisin, heart, and blood vessels

CVD remains a major contributor to global mortality [101]. It is well known that exercise lowers the risk of CVD, with more recent studies showing that irisin is lower in patients with CVD than in those without [102, 103, 104]. The pronounced effect of irisin on cardiac muscle may be explained by its higher baseline expression in cardiac tissue compared to skeletal muscle, with exercise further amplifying its production in the heart [105].

More specifically, irisin level was found to be low in myocardial infarction (MI) [106, 107] and may be explained by a lack of activity after an acute coronary event. Moreover, in the case of MI, treatment with irisin leads to myocardial regeneration, increased neovascularization [106], and an increase in end-diastolic volume, heart rate, and cardiac output [108].

Regarding atherosclerosis, the same trend is observed with lower values for irisin [109, 110, 111]. However, the administration of irisin improves endothelial dysfunction and decreases endothelial apoptosis [9].

Irisin and bone tissue

The role of exercise in improving bone structure is well known. Sedentary lifestyles lead to an imbalance in bone formation and resorption, tilting in favor of bone resorption [30]. The scientific community is seeking to understand how exercise prevents the onset of OP, with a particular interest in the myokines released during exercise.

Studies show that exercise reduces the risk of OP by increasing the secretion of myokines, which facilitate communication between skeletal muscle and bone tissue via endocrine pathways [112].

More than 650 myokines have been identified, with irisin being one of them [112]. They play an important role in providing energy during exercise, communicating with adipose tissue, bone, liver, intestine, pancreas, brain, skin, blood vessels, and also as antitumor agents [112].

Irisin is attracting increasing attention among these myokines due to its pleiotropic effects. Many studies have shown that irisin decreases with age and in patients with bone disease, including primary and secondary OP [43]. Some studies have shown exciting findings on irisin administration in mice concerning bone mass and mineral density [39]. Colaianni et al. investigated cortical and trabecular regions of the tibia after administration of 100 μg/kg recombinant (r)-irisin per week. They detected major changes, particularly in the cortical bone, with a significant increase in mineral density and strength, but also increased osteopontin levels and decreased sclerostin levels [35]. The lack of irisin was investigated by Luo et al., who showed that FNDC5 knockout (KO) mice manifest reduced bone mass and strength, increased osteoclast numbers, and receptor activator of nuclear factor kappa-Β ligand (RANKL) expression. Proinflammatory markers such as IL-6 and tumor necrosis factor-alpha (TNF-α) were also increased in irisin-deficient mice [59].

Irisin and intestinal diseases

The administration of irisin in patients with acute or chronic pancreatitis has been found to have protective effects on irisin levels [113]. In vitro studies have shown that irisin inhibits the growth, migration, and invasiveness of pancreatic cancer cells by acting on AMPK–mechanistic target of rapamycin (mTOR) signaling pathway [114].

Shahidi et al. compared irisin levels in individuals without gastric cancer (GC) and patients with GC and correlated irisin levels with oxidative stress. Significantly high levels of irisin are found in patients with GC, suggesting its potential as a marker for early diagnosis [115].

As far as colorectal cancer (CRC) is concerned, it is well-known that obesity is a risk factor. Reduced irisin levels in patients with CRC were identified in a study that included 76 such patients and 40 healthy subjects [116]. Another study using immunohistochemistry demonstrated higher levels of irisin in the initial stages of colorectal adenocarcinoma than in the advanced disease [113].

Irisin and kidney

The kidneys are the primary source of diabetes complications [34]. Irisin levels are lower in patients with microalbuminuria and macroalbuminuria than in those without [45]. As proteinuria levels increase and renal filtration rate decreases, irisin levels decrease [117]. The treatment of mice with Cyclo(RGDyK), an irisin receptor blocker, inhibited the beneficial effects of aerobic exercise, such as reducing albuminuria, glomerular hypertrophy, and renal inflammation [40, 118]. Furthermore, the activation cascade of the irisin–AMPK–sirtuin 1 (SIRT1)–PGC-1α signaling pathway, inhibiting acyl-coenzyme A (CoA):lysocardiolipin acyltransferase-1 (ALCAT1) expression and reducing oxidative stress and apoptosis, was observed to be stimulated by aerobic exercise [46]. Increased PGC-1α expression suppresses irisin expression and inhibits transforming growth factor-beta (TGF-β) type 1 receptor (TGFBR1) activation in renal tubular cells, thereby enhancing energy metabolism and reducing renal fibrosis [44]. Moreover, irisin binds to the TGF-β type 2 receptor (TGFBR2), which subsequently interferes with TGF-β1-mediated phosphorylation of Smad2/3 [44]. Irisin exerts its beneficial effects at the renal level by inhibiting TGF-β1 and Smad2/3 [119].

Could account for decreased irisin levels in chronic kidney disease (CKD): decreased muscle mass, especially in the later stages of CKD [120], reduced FNDC5 expression as a result of uremic toxins (indoxyl sulfate) [121], increased level of inflammation with increased reactive oxygen species (ROS) [34].

Irisin and inflammation

Sedentary lifestyles are involved in the pathogenesis of many chronic diseases, such as obesity, T2DM, CVD, immunological dysfunction, bronchial asthma, neurological disorders, etc. Most of these pathologies are associated with a degree of persistent chronic inflammation [36]. Exercise improves immune system activity and reduces systemic inflammation [122].

More specifically, exercise increases phagocytosis, stabilizes atheroma plaque in apolipoprotein E-deficient mice, and reduces oxidative stress and macrophage infiltration [123]. In obese individuals, adipocytes release several proinflammatory cytokines such as TNF-α, IL-6, and IL-17A [124]; adipose tissue becomes loaded with M1-type macrophages, and the number of M2-type macrophages decreases, leading to an even more significant increase in proinflammatory cytokines [34]. There is evidence that irisin causes attenuation of this systemic inflammation, with irisin being negatively correlated with highly sensitive protein C [66]. Irisin treatment reduces the inflammatory marker levels, such as IL-6, TNF-α, macrophage inflammatory protein (MIP)-1α, and MIP-1β, thereby increasing the percentage of M2 macrophages [125, 126]. The anti-inflammatory role of irisin is not only related to obesity, but it is also documented in T2DM, CVD, NAFLD, and cancer [126].

Approaches in the study of irisin

There are three primary methods for measuring irisin: ELISA, Western blot, and mass spectrometry (MS). MS is considered the most widely accepted in measuring irisin values [38]. However, all three methods are subject to methodological problems and do not provide reliable and reproducible data [43].

Conclusions

Irisin is a key myokine involved in activating brown adipose tissue, improving carbohydrate homeostasis, promoting synaptic transmission, maintaining musculoskeletal homeostasis, and inhibiting carcinogenesis. In general, the mechanism of action of irisin involves interaction with the αv/β1/5 integrin-like receptor, which activates the AMPK, FAK, and other pathways. However, it is worth noting that the literature comprises studies conducted on small cohorts, each with distinct characteristics. Additionally, the lack of standardized quantitative tests for irisin should be considered, given the significant variability in reported reference values in serum, which range from pg/mL to μg/mL. It is well known that exercise contributes to overall well-being, including improved energy levels, sleep quality and reduced disease risk. Increasingly, researchers are beginning to believe that these beneficial effects can be at least partially attributed to the irisin molecule. Still, the potential of this substance remains to be validated in future studies.

Conflict of interests

The authors declare that they have no conflict of interests.