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Biochemistry & Molecular Biology
Adipose, skeletal, and hepatic muscle tissues are the main endocrine organs that produce adipokines, myokines, and hepatokines. These biomarkers can be harmful or beneficial to an organism and still perform crosstalk, acting through the endocrine, paracrine, and autocrine pathways. This study aims to review the crosstalk between adipokines, myokines, and hepatokines. Far beyond understanding the actions of each biomarker alone, it is important to underline that these cytokines act together in the body, resulting in a complex network of actions in different tissues, which may have beneficial or non-beneficial effects on the genesis of various physiological disorders and their respective outcomes, such as type 2 diabetes mellitus (DM2), obesity, metabolic syndrome, and cardiovascular diseases (CVD). Overweight individuals secrete more pro-inflammatory adipokines than those of a healthy weight, leading to an impaired immune response and greater susceptibility to inflammatory and infectious diseases. Myostatin is elevated in pro-inflammatory environments, sharing space with pro-inflammatory organokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), resistin, and chemerin. Fibroblast growth factor FGF21 acts as a beta-oxidation regulator and decreases lipogenesis in the liver. The crosstalk mentioned above can interfere with homeostatic disorders and can play a role as a potential therapeutic target that can assist in the methods of diagnosing metabolic syndrome and CVD.
- adipokines
- myokines
- hepatokines
- metabolism
- cardiovascular diseases
1. Introduction
Eating behavior, delimited by cultural and social aspects, has a substantial impact on health conditions and the development of cardiovascular diseases and inflammatory complications [1]. The popularity of cheap, high-calorie foods associated with sedentary living, high workload, and time constraints has contributed substantially to the global increase in obese individuals. The excess weight combined with hyperglycemia predisposes oxidative stress and inflammation [2] can impair insulin signaling and promote the development of comorbidities, such as type 2 diabetes mellitus (DM2), hypertension, and other factors that induce cardiovascular complications. [2]. In accordance with the International Obesity Task Force, an estimated 1.7 billion people are vulnerable to health risks determined by body weight. Moreover, 2.5 million deaths annually are related to the increase in the body mass index (BMI), which is expected to double by 2030 [3].
These changes in lifestyle habits have allowed cardiovascular disease (CVD), especially coronary artery disease, stroke, and heart failure, to occupy the number one position among the leading causes of death worldwide today [4,5]. According to the World Health Organization (WHO), CVDs are responsible for approximately 17.9 million deaths per year, corresponding to 31% of total deaths worldwide in recent decades, in addition to being responsible for increased morbidity and lifelong disability [6]. The increases in these mortality and morbidity rates are interpreted as a trend in developed and developing countries due to the difficulty in modifying the consolidated lifestyle habits and the several associated comorbidities that hinder the prognosis and perpetuate cardiovascular risks. From this perspective, CVDs are real burdens for health systems due to their severity, prevalence, and difficulty to treat [7].
In contrast, technological advances in medicine have raised quality and life expectancy, giving light to another trend in the contemporary world: population aging. However, physiological changes inherent to the aging process, such as sarcopenia, decreased cardiovascular, and cognitive function, added to the population’s bad habits, seem to predispose the body to more significant cardiovascular risks and other chronic diseases associated with aging [8]. Therefore, physical activity and good eating habits must be encouraged to achieve healthy aging. Otherwise, without a doubt, such situations tend to compromise further the overload of health systems and the daily challenge of professionals [9].
In the molecular context, organokines are increasingly investigated because they are related to metabolism. Adipose, skeletal, and hepatic muscle tissues are the main endocrine organs that produce adipokines, myokines, and hepatokines. These biomarkers can be harmful or beneficial to the organism and still perform crosstalk, acting through the endocrine, paracrine, and autocrine pathways. Therefore, they have specific associations with insulin resistance, diabetes mellitus, obesity, metabolic syndrome, and CVD [10]. Thus, adipokines, myokines, and hepatokines may play, in the near future, roles of new markers for diagnosis and prognosis, elucidating the mechanisms involved in metabolic disorders and CVD, thereby facilitating innovative therapeutic approaches [11].
The gathering of knowledge about adipokines, myokines and hepatokines and the cross-talk between them, brings to light the understanding of how lifestyle changes leading to obesity and its metabolic consequences, results in marked changes in the secretion profile of these substances, which may be the basis of many disorders. Moreover, many organokines are secreted by all three tissues. Therefore, understanding the mechanisms involved in the secretory pattern can be useful in the investigation of many diseases.
2. Discussion
2.1. Adipokines
Adipokines are molecules released by adipose tissue through endocrine pathways, capable of controlling lipid metabolism and interfering with insulin sensitivity, appetite, fibrogenesis, and liver fat deposition. Leptin and adiponectin (Table 1) are the classic adipokines of adipose tissue and have a substantial relationship in the pathogenesis of obesity and metabolic complications [12]. Adipose tissue responds to excess energy through energy storage by increasing adipocytes. In obesity, its hypertrophy is directly related to chronic low-grade inflammation and an increase in chemotactic molecules, in addition to a reduction in adiponectin levels and the onset of leptin resistance. With the increase in adipose tissue, mainly in the visceral region, there is a change in the expression pattern of M1 macrophages that are related to gene modulation and the consequent increase in the release of pro-inflammatory mediators, such as leptin (there will be resistance to the action of leptin), resistin, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-18, plasminogen activator inhibitor (PAI-1), and reduction in anti-inflammatory mediators such as IL-10 [10,11,13]. Table 1 shows the main characteristics of classic adipokines in adipose tissue.
Table 1. Main characteristics of the adipokines.
| Adipokine | Stimulation for Its Increase | Metabolic Action | Reference |
|---|---|---|---|
| Leptin | Increase in fat mass. | In the immune system, it acts to increase pro-inflammatory cytokines. In the CNS, it promotes a decrease in food intake and an increase in global energy expenditure. In skeletal muscle, it acts in the absorption and oxidation of glucose and FFA. In the liver it increases the oxidation of fatty acids and reduces the accumulation of lipids. | [11] |
| Adiponectina | Adrenergic beta signaling; increase in FGF21, IL-15, and irisin induced by physical exercise. | In the immune system it has anti-inflammatory actions. In the CNS it promotes an increase in food intake and a reduction in hypothalamic inflammation. In the liver and skeletal muscle, it increases fatty acid oxidation and insulin sensitivity. | [11] |
| Resistin | Increase in fat mass. | Immune system: pro-inflammatory actions. It acts in endothelial dysfunction, CVD and inhibition of insulin signaling through the suppressor of cytokine signaling 3 (SOCS3). | [14,15] |
| IL-6 | Activation of the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB). | Adipose tissue: proinflammatory action, and acts in inhibiting the expression of insulin receptor substrate 1 (IRS1) and glucose transporter type 4 GLUT4) in adipocytes. | [14] |
| Asprosin | Induced by fasting and produced by white adipose tissue in obese people with DM2. | It increases food consumption and body weight and accelerates the production of liver glucose. | [16,17] |
| Chemerin | Inflammatory and coagulation serine proteases. | It accentuates glucose intolerance and makes insulin signaling difficult. | [18] |
| Omentin | Increase in FGF21 and dexamethasone. | Optimizes the action of insulin and, consequently, the absorption of glucose. It also acts as an anti-atherosclerotic factor. | [19] |
| FGF21 | Exposure to cold and physical exercise. | It acts in the browning of WAT, lipid oxidation and thermogenesis, and stimulates the expression of adiponectin in the bloodstream. | [20] |
| SFRP5 | Induced during the proliferation, differentiation and maturation of pre-adipocytes. | Regulates the expression of pro-inflammatory cytokines by inhibiting the Wingless-type family member 5a signaling (Wnt5a), non-canonical Wnt family. | [14,21] |
| Lipocalin 2 | Low-level systemic inflammation in obese patients with metabolic syndrome. | Regulation of inflammation and the transport of fatty acids and iron. It is associated with CVD, vascular remodeling and instability of atherosclerotic plaques. | [22,23] |
| Vaspin | Increase in fat mass. | Reduces the synthesis of pro-inflammatory cytokines. It improves glucose intolerance and insulin sensitivity and protects the vascular tissues from fatty acid-induced apoptosis. | [24,25] |
| FSTL1 | It is expressed in large quantities by adipose tissue in the state of low-grade chronic inflammation. | Lower levels of FSTL1 are associated with super obesity due to loss of adipogenesis, increased maturated adipocytes, cellular senescence and anti-apoptotic FSLT1 reduction. It has a pro-inflammatory action and possible relationship with overweight and obesity. | [26] |
| Sparc | Secreted by adipocytes, promoted adipose tissue fibrosis and inhibited adipogenesis. | Responsible for modulating the expression of pro-inflammatory cytokines that act on insulin resistance; and inhibits adipogenesis. | [23,27] |
| CTRPs | Expressed in conditions of adiponectin and leptin deficiency and high body mass index. | Regulation of inflammatory processes of adipose tissue. Regulation of glucose and fat metabolism in peripheral tissues and food intake. | [23,28] |
| FAM19A5 | Increase in fat mass. | Inhibits the proliferation and inflammation of vascular smooth muscle cell related to cardiovascular diseases through obesity. | [29] |
| WISP1 | Obesity, adipogenesis and visceral fat abnormalities. | Stimulates the cytokine response in macrophages associated with tissue adipose; induces the proliferation of mesenchymal stem cells, which increases tissue adipose. | [30] |
| Progranulin | Increase in fat mass associated with obesidade visceral, DM2 and dislipidemia. | It has anti-inflammatory properties. Hyper-progranulinemia is associated with insulin resistance and deficient insulin signaling. | [31,32] |
| Nesfatin-1 | Unclear | Induces satiety, which promotes body weight reduction. It can also regulate gastric distension and motility via the melanocortin pathway in the central nucleus of amygdala. | [23] |
| Visfatin | Increase in fat mass. | It produces adipocyte inflammation, insulin resistance and pancreatic beta cell dysfunction. | [33,34] |
| Fetuin-A | Increase in fat mass. | Associated to insulin resistance and inflammation. | [35] |
| ZAG | PPARγ, glucocorticoids, certain β3-adrenergic receptor agonists, thyroid hormones, and growth hormone (GH). | It acts in the acceleration of lipid metabolism, regulating enzymes of lipogenesis and lipolysis and stimulating production of adiponectin and BAT. | [36,37,38] |
BAT: brown adipose tissue; CNS: central nervous system; CTRPs: C1q/TNF-related proteins; CVD: cardiovascular disease; DM2: diabetes mellitus type 2; FAM19A5: family with seuence similarity to 19 member A5; FFA: free fatty acid; FGF21: fibroblast growth factor 21; FSTL1: follistatin-like 1; IL: interleukin; SFRP5: secreted frizzled-related protein 5; Sparc: secreted protein acidic and rich in cysteine; TNF-α: tumor necrosis factor-alpha; ZAG: zinc-α2-glycoprotein; WAT: white adipose tissue; WISP1: wingless-type inducible signaling pathway protein-1.
2.2. Myokines
In addition to playing important roles as a reservoir and consumer of energy and a leading role in carbohydrate metabolism, skeletal muscle tissue (SkM) has been associated with substantial secretory functions in recent studies. These secretion products, called myokines, are peptides, cytokines, or growth factors that show a diversity of autocrine, paracrine, or endocrine actions. These molecules are expressed mainly in physical activities or absence, allowing its communication with other body tissues, thereby showing actions that can be considered beneficial for most myokines or related to metabolic dysfunctions [8,14]. A vast number of myokines were identified, although other tissues also produce some. Each myokine appears to be related to a specific type of muscle fiber and different physical exercise modalities [56] (Table 2).
Table 2. Main characteristics of the myokines.
| Myokine | Stimulation for Its Increase | Metabolic Action | Reference |
|---|---|---|---|
| Irisin | Physical exercise. | Darkening of WAT, increases energy expenditure, improves insulin sensitivity and induces weight loss. | [8] |
| BAIBA | Aerobic exercise | It acts in the Browning of adipose tissue, lipid oxidation and reduces insulin resistance. | [11] |
| Myostatin | Sedentary lifestyle | Induces muscle mass loss associated with insulin resistance and fat accumulation in the liver. Facilitates body fat accumulation. | [45] |
| Follistatin | Expressed in the context of physical activity, especially aerobic, resistance or high intensity training. | Inhibits the actions of myostatin, contributing to hypertrophy of skeletal muscle and reduction in fat mass, with consequent optimization of glucose uptake. | [13] |
| FGF21 | Physical exercise. | Increases insulin sensitivity, reduces plasma glucose and acts on lipolysis. | [57] |
| Apelin | Resistance exercises. | Anti-inflammatory role. It acts in the formation of new vessels and in the control of cardiac muscles and blood pressure. | [58] |
| Myonectin | Resistance exercises. | Increases the uptake of lipids by adipose tissue and liver, decreasing the plasma concentration of FFA. | [20] |
| IL-6 | Physical exercise. | Pro-inflammatory cytokine associated with insulin resistance in obesity. | [59] |
| IL-15 | Released after acute episodes of aerobic exercise. | Anti-inflammatory properties by inhibiting TNF-α expression; contributes to muscle hypertrophy, reduction in visceral adipose tissue and optimizes insulin action. | [14] |
| Sparc | Resistance exercises and muscle hypertrophy. | Inhibition of adipose tissue formation, increased insulin release and optimization of glucose uptake. | [60] |
| BDNF | Muscle and brain induced after exercise. | When produced by muscle, it increases sensitivity to insulin. | [61] |
| METRNL | Resistance exercises. | Anti-inflammatory role. Contributes to the browning of WAT and energy expenditure through the oxidation of glucose and FFA. | [62] |
| Decorin | Expressed in response to acute or chronic endurance training | Binds to myostatin by inhibiting its actions. As a consequence, it induces hypertrophy in the skeletal muscle. | [63] |
BAIBA: β-aminoisobutyric acid; BDNF: brain-derived neurotrophic factor; FFA: free fatty acid; FGF21: fibroblast growth factor 21; IL-6: interleukin 6; IL-15: interleuckn 15; METRNL: meteorin-like protein; Sparc: secreted protein acidic and rich in cysteine; TNF-α: tumor necrosis factor-α; WAT: white adipose tissue.
2.3. Hepatokines
Hepatokines are proteins produced by the liver that have recently been discovered as new hormones, which can worsen or improve metabolic conditions [64]. Such situations are regulated via autocrine, paracrine, and endocrine both in the liver and other tissues [18]. Even so, there is a greater interference of hepatokines in the fatty and striated skeletal muscle tissue, showing an endocrine-dependent relationship, therefore acting through crosstalk with the cytokines released by these respective tissues [14]. Table 3 brings the role of some hepatokines.
Table 3. Main characteristics of the hepatokines.
| Hepatokine | Stimulation for Its Increase | Metabolic Action | Reference |
|---|---|---|---|
| Fetuin A | Related to obesity, especially NAFLD and the increase in VAT. | It causes injury to the pancreas B cells and insulin resistance and works as a predictor of DM2. | [59,65] |
| Fetuin B | Increased in humans with steatosis and is related to insulin resistance. | Promotes insulin resistance and the development of diabetes. | [66] |
| Adropin | Regulated positively with food intake and weight reduction. | Stimulates lipolysis throughout the body, reducing weight gain and hepatic steatosis, optimizing the action of insulin and preventing the progression of atherosclerosis. | [67] |
| Activin E | High with obesity and NAFLD. | Reduces lipolysis and increase fat accumulation in adipocytes. | [68,69] |
| SHBG | Weight reduction and healthy lifestyle. | Transport of sex steroids to its target tissues. The increase in insulin sensitivity, stimulated by SHBG, is not yet fully cleared. | [70,71] |
| Chemerin | Produced in a state of obesity, dyslipidemia, metabolic syndrome and DM2. | Impairment of glucose homeostasis, increases insulin resistance and fat accumulation in the liver. | [14,72] |
| Selenoprotein | Associated with metabolic diseases, insulin resistance and hypoxia. | Attenuates fat loss induced by exercise. In hypoxia, insulin resistance and fat accumulation in adipose tissue increases. | [11,73] |
| Folistatin | It increases when the glucagon-to-insulin ratio rises in situations of aerobic exercise and resistance. | Actions on skeletal muscle hypertrophy, which increases glucose capture, and on the expression of thermogenic genes in murine adipocytes. | [11,74] |
| FGF21 | Aerobic exercises | It increases the sensitivity to insulin, the oxidation of fatty acids in the liver, decreases the production of glucose and the development of hepatic steatosis. | [11] |
| ANGPTL4 | Physical exercise | Stimulates lipolysis and decreases the action of the LPL enzyme on white adipose tissue. Inhibits pancreatic lipase and consequently decreases fat absorption. | [11,75] |
| ANGPTL4 | Food signals | Mediates food-driven resetting of circadian clock in mice liver; associated with regulation of inflammation, lipid metabolism, cancer cell invasion, and hematopoietic stem activity | [76] |
| LECT2 | Associated with metabolic stress | Impairment of insulin signal transduction and increases the appearance of pro-inflammatory cytokines. | [67] |
| Hepassocin | Elevated in pre-diabetes, DM2, and NAFLD. | Participates in the regulation of hepatocyte proliferation and liver regeneration. | [67,77] |
| Tsukushi | In response to NAFLD. | Reduces HDL-c cholesterol; reduced cholesterol efflux capacity, and reduces cholesterol-to–bile acid conversion in the liver. | [78] |
ANGPTL4: angiopoietin-like 4; DM2: diabetes mellitus typo 2; FGF21: fibroblast growth factor 21; LPL: lipoprotein lipase; LECT2: leukocyte cell-derived chemotaxin 2; NAFLD: nonalcoholic fatty liver disease; SHBG: sex hormone-binding globulin; VAT: visceral adipose tissue.
2.4. Adipokines, Myokines and Hepatokines: Crosstalk and Metabolic Repercussions
Far beyond understanding each adipokine, myokine, or hepatokine’s actions alone, it is important to underline that these cytokines act together in the body, forming a complex network of actions in different tissues, which may have beneficial or non-beneficial effects on the genesis of various physiological disorders, and their respective outcomes, such as DM2, obesity, metabolic syndrome, and CVD [10]. Understanding this crosstalk and the subsequent pathophysiological mechanisms is valid for establishing future preventive and therapeutic measures to better manage the involved complications [59].
Present at the origin of several metabolic disorders, myostatin has negative effects on metabolism, and its levels are increased with physical inactivity and high levels of fat mass. Thus, myostatin is elevated in pro-inflammatory environments, sharing space with pro-inflammatory organokines such as TNF-α, IL-1, resistin, chemerin, and others [92]. Its contribution to resistance to the action of insulin occurs due to the decrease in phosphorylation of insulin receptor, compromising the entire insulin signaling pathway necessary to trigger its cellular actions [11]. Thus, the uptake of glucose by insulin-dependent tissues, such as skeletal muscle and adipose tissue, becomes impaired, promoting the state of hyperglycemia and allowing tissues such as those of the liver to capture the excess of glucose that will later be accumulated in the form of fat, characterizing hepatic steatosis [45].
In parallel, myostatin promotes the state of obesity, sarcopenia, and sarcopenic obesity, which promotes the release of inflammatory adipokines and hepatokines while inhibiting the release of myokines and other anti-inflammatory and antioxidant organokines [14]. Thus, myostatin, TNF-α, leptin, resistin, chemerin, fetuin-A, and other cytokines build an inflammatory and oxidative stress scenario from the polarization of macrophages (M ϕ) M1 in adipose tissue, production of reactive oxygen species, decreased insulin action, and release of FFA in plasma [11]. The hemodynamic pattern and vascular endothelial function are also altered with the pro-inflammatory secretory pattern. These cytokines, especially TNF-α and leptin, seem to aggravate hypertension, which, together with visceral obesity, dyslipidemia, and hyperglycemia, configure the metabolic syndrome scenario [59,93].
There is a wide range of disturbances in glucose and lipid homeostasis. Oxidative stress and the inflammatory state act overtime, promoting endothelial dysfunction. Hyperglycemia contributes to the production of advanced glycation end products (AGES), which, together with reactive oxygen species, cause endothelial damage, while adhesion molecules and immune cells are attracted to the vascular bed [94]. This environment constitutes fertile soil for atherosclerosis’s chronic inflammatory process, a prelude to several cardiovascular conditions [8]. Therefore, it is worth noting that myostatin has a role as a therapeutic target for managing these aforementioned metabolic disorders [45]. Many studies point to a decrease in myostatin through physical exercise, with positive effects in combating insulin resistance and reducing fat accumulation and muscle hypertrophy [95].
An important contribution to excess adiposity and favoring insulin resistance is the deregulation of the secretion and production of adipokines and myokines [96]. Adipo-myokines, such as IL-6 and TNF-α, secreted from muscle cells and adipocytes, if chronically elevated, can induce insulin resistance and consequently other comorbidities [92]. In obese and diabetic individuals, visceral fat is related to the expression of IL-6 and TNF-α produced by macrophages that prevent or attenuate insulin signaling in insulin-dependent tissues. Despite this, IL-6 released during physical exercise can improve glucose and lipid metabolism, while plasma levels of TNF-α in exercise are reduced, although its expression in adipose tissue is not affected [14].
In addition to being involved in disease metabolism, adipokines can modulate bone mineral density and bone turnover as well as skeletal muscle catabolism in aging [97]. In muscle aging, increased plasma levels of IL-6 and TNF-α, associated with loss of muscle strength, activate cell signaling pathways that lead to skeletal muscle atrophy, which in turn induce resistance to IL-6, a condition that shares similarities with insulin or leptin resistance [98]. In obesity, leptin resistance caused by hyperleptinemia can limit muscle fatty acid oxidation and reduce lipolysis of adipose tissue. This effect is neutralized with physical exercise and aggravated by an unhealthy lifestyle, as the pro-inflammatory state results in crosstalk that exacerbates the disease’s progression [99,100].
For these reasons, physical exercise is a powerful ally in the prevention and improvement of the prognosis of cardiovascular diseases, DM2, and obesity, since it influences the predominance of the secretion of anti-inflammatory myokines, adipokines, and hepatokines, such as irisin, IL-6, IL -15, myonectin, adiponectin, FGF21 (which mitigate the harmful effects of myostatin), TNF-α, resistin, chemerin, fetuin-A, and other cytokines [101]. Together, these cytokines induced in a healthy environment optimize the secretion and action of insulin; favor energy expenditure; reduce the storage of visceral fat; and, consequently, stimulate polarization of MϕM2 and reduction in Toll-like receptors (TLRs), decreasing the inflammatory pattern [11,102]. Beyond that, these cytokines appear to exhibit a protective effect on the endothelium and vascular smooth muscle, preventing atherosclerosis [103].
Studies indicate that the disproportionate release of pro-inflammatory adipokines and the reduction in lipolysis are simultaneous with insulin resistance, which plays a substantial role in the development of DM2. Insulin suppression leads to an increase in plasma fatty acid and consequent absorption by liver and muscle tissue, creating intracellular lipotoxic environments that prevent the translocation of GLUT4 in skeletal muscles and adipose tissue [104,105]. Substances that act as adipokines, myokines, and hepatokines, such as FGF21, are essential for controlling glucose and lipid metabolism. FGF21 controls insulin sensitivity by improving fat oxidation in the muscle, de novo lipogenesis (DNL) in the liver, and thermogenesis in WAT and BAT. As such, it is an important therapeutic target of protection against muscle and liver insulin resistance induced by lipids and DM2 [106,107].
It is well known that obesity, insulin resistance, and inflammation are risk factors for several metabolic disorders [108]. Overweight individuals secrete more pro-inflammatory adipokines, leading to an impaired immune response and greater susceptibility to inflammatory and infectious diseases [109]. Elevated levels of leptin and chemerin, for example, may be negatively associated with cardiometabolic health, just as adiponectin and omentin-1 may be positively associated. Therefore, the assessment of circulating adipokines may be relevant in the analysis of cardiometabolic risk [110].
In the same way that FGF21 is classified as myokine and adipokine, when working as an hepatokine, it acts as a beta-oxidation regulator and decreases lipogenesis in the liver, especially when it increases in the post-exercise period [11]. In clinical studies, patients who had DM 2 were treated with concentrations of FGF21 (with the analog LY2405319), and they showed a reduction in low-density lipoprotein (LDL) cholesterol and triglycerides, an increase in high-density lipoprotein (HDL) cholesterol, and an improvement in insulin during periods of fasting [75]. It was also shown that they identified a less atherogenic apolipoprotein profile, reducing cardiovascular risks and promoting improvements in body weight and adiponectin levels [67].
When activated by exercise, follistatin inactivates myostatin and, therefore, inhibits its pro-inflammatory effects, consequently cooperating with lipolysis in WAT. It has also been identified that follistatin directly protects β cells when induced by exercise, together with irisin [11]. However, circulating follistatin was elevated in patients with DM2 and generally correlates with insulin resistance markers, such as fasting glucose, glycated hemoglobin, and 2-h glucose during an oral glucose tolerance test [111].
Subsequently, the hepatokine most positively associated with CVD is adropin. It is expressed in endothelial cells and promotes essential functions, such as proliferation, migration, and formation of the capillary tube, together with attenuation of vascular permeability and TNF-α-induced apoptosis. Therefore, adropin is considered a protective factor of the endothelium, which increases the synthesis of nitric oxide (NO) due to the activation of eNOS. As a result, plasma levels of adropin increase with physical training and culminate with the suppression of atherosclerosis due to the regulation of monocyte differentiation, precisely its anti-inflammatory type. In this scenario, it was also observed that adropin increases fibronectin and elastin expression in vascular smooth muscle cells (VSMCs) by overloading the PI3K-Akt pathway, thus assuming that adropin regulates plaque stability and elasticity vascular [112].
On the other hand, a case–control study showed that adropin levels decreased in patients with NASH and were negatively related to serum levels of alanine transaminase, aspartate aminotransferase, and gamma glutamyl transpeptidase. It is also negatively related to the pathological changes in NAFLD, suggesting that the lower adropin expression may play an important role in the progression of NAFLD to severe NASH. Finally, another factor that implies a reduction in adropin is the oxygen-relative species, which can also culminate in NAFLD progression [113].
The main hepatokines related to insulin resistance, a fundamental factor in the development of DM2 and obesity, are fetuin-A, hepassocin, LECT2, and selenoprotein. They are usually elevated when associated with these pathologies and contribute to a state of systemic inflammation [88]. In addition to insulin resistance, fetuin-A can also promote lipotoxicity in β cells through the TLR4-JNK-NF-kB signaling pathway [65]. Finally, fetuin-B also negatively impacts metabolism because its serum level is higher in patients with coronary artery disease, especially in those with the acute coronary syndrome, and it still positively correlates with LDL-c levels [114].
Figure 4 shows some associations among adipokines, myokines and hepatokines.
Figure 4. An overview of the crosstalk between adipokines, myokines and hepatokines. Adipokines are represented in brown, myokines in green and hepatokines in blue. The arrows that are indicating upward indicate an increase and downward decrease. (x) represents inhibition and (+) activation. Blue arrows are associated with benefits, while red arrows are associated with harm aspects. IL: interleukin; BDNF: brain-derived neurotrophic factor; FGF-21: fibroblast growth factor-21; SkM: skeletal muscle; WAT: white adipose tissue; CVD: cardiovascular disease; LECT2: leukocyte cell-derived chemotaxin 2; FFA: free fatty acid.
This entry is adapted from the peer-reviewed paper 10.3390/ijms22052639
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