Table of Contents

    Topic review

    Physical Exercise in NAFLD

    Subjects: Nursing | Physiology
    View times: 71

    Definition

    Non-alcoholic fatty liver disease (NAFLD) is a major health problem, and its prevalence has increased in recent years. Diet and exercise interventions are the first-line treatment options. The goal is to understand the complex pathophysiology underlying exercise interventions with the potential to prevent and treat NAFLD.

    1. Introduction

    Nonalcoholic fatty liver disease (NAFLD) is a common disease in one-third of the population in developed countries. NAFLD is associated with metabolic abnormalities including obesity, type 2 diabetes (T2DM), insulin resistance, and cardiovascular disease [1]. NAFLD is a spectrum of liver disease that ranges from simple hepatic steatosis to steatohepatitis (NASH) which is characterized by hepatocyte degeneration (ballooning) and inflammation with or without fibrosis. A small proportion of NASH will further progress to liver cirrhosis and hepatocellular carcinoma [2][3].

    Diet has a key role in the development of NAFLD. Genetic and positive energy balance have important impacts on the first “hit” and diet composition affects the second "hit" and the severity of NAFLD [4][5][6] emphasizing the criticality of management and control of NAFLD. Several studies have reported that excessive consumption of carbohydrates, especially refined carbohydrates, fats, saturated fats in particular, and protein from meat can cause NAFLD [7][8]. Besides, higher intakes of soft drinks are associated with fatty liver [9].

    At present, there is no clear consensus on the pharmacological treatment of NAFLD. In fact, no effective therapeutic agents have been approved for the treatment of the disease. Nevertheless, it is clear that therapeutic approaches should focus on lifestyle modifications. Diet and exercise interventions are the first-line treatment options, with weight loss via a hypocaloric diet being the most important therapeutic target in NAFLD [10]. However, most NAFLD patients are not able to achieve such weight loss. Therefore, the requisite is the investigation of other effective therapeutic approaches. Nutrient composition and caloric intake have been used to devise optimized diets in different stages of NAFLD to control disease progression [11]. Recently, it is recognized that timing and/or frequency of eating meal and fasting (with or without reduced energy intake) can have profound health benefits [12][13]. Nevertheless, more research should be focus on understanding the pathophysiology of the different strategies integrating nutrients, food intake and patterns of frequency of eating meals to provide recommendations for the prevention and treatment of NAFLD.

    On the other hand, both aerobic and resistance exercise training in the absence of weight loss has been shown to reduce intrahepatic lipid (IHL) in patients with NAFLD [14]. However, whether exercise training without weight loss can reduce the histological features of NASH and fibrosis remains unknown [15]. Clearly, more studies are required to explore further the molecular and cellular mechanisms involved and to define the optimal volume and intensity of exercise, and whether weight loss is required for histological improvement in NASH and fibrosis.

    2. Exercise Activates Liver-Muscle Signaling Pathways Involved in NAFLD

    Physical activity induces a complex system of communication between muscle and liver [16][17]. This communication increases amino acid metabolism, especially branched chain amino acids from muscle and regulates metabolic activities in the liver that induce lipolysis. Exercise not only induces the release of signaling substances such as myokines from muscle [17], but also induces the release of other substances from the liver that control metabolic processes both in the liver and the rest of the organism [16][18].

    Some of the main aspects of these mediators and their relationship with NAFLD (Figure 1).

    Figure 1. Liver/muscle crosstalk in NAFLD (Non-Alcoholic Fatty Liver Disease). Exercise induces the release of several signaling molecules from liver (hepatokines) that, through an endocrine mechanism, improves the physiology of muscle. On the other hand, exercised muscle releases into the circulation other substances called myokines that influence liver physiology, improving the situation caused by NAFLD. Both, hepatokines and myokines reduce the levels of pro-inflammatory markers (see complete names in text). In red, compounds that increase with exercise; in green, compounds that decrease with exercise; in black, compounds with conflicting responses to exercise.

    2.1. Hepatokines

    Hepatokines are proteins secreted by hepatocytes that influence metabolic processes through autocrine, paracrine and endocrine signaling [19]. NAFLD produces changes in the secretion of these proteins that can increase insulin resistance and induce metabolic dysfunction in many other tissues [20]. Among others, these hepatokines are follistatin (FST), fetuin A and B, retinol-binding protein 4 (RBP4) and selenoprotein P (SeP). NAFLD not only induces changes in the secretion of hepatokines but also produces changes in metabolites, lipids and miRNAs that can alter the metabolism in peripheral tissues including skeletal muscle [21].

    2.1.1. Fibroblast Growth Factor 21

    Fibroblast growth factor-21 (FGF-21) is a 24-kDa protein that binds to the classic FGF receptor and the FGF-co-receptor β-klotho [20]. FGF-21 is highly expressed in the liver [22]. FGF-21 is associated with the regulation of energy metabolism, since FGF-21 null mice suffer impairment of glucose metabolism, maladaptation to ketosis and excessive body weight [23]. Furthermore, these mice showed increased hepatic steatosis [24] and inflammation in an IL-17S-TLR4 dependent manner [25], indicating its importance in the impairment of NAFLD.

    Although FGF-21 was initially considered as a myokine [26], some research has demonstrated its release from liver after endurance exercise [27]. Other studies have indicated that FGF-21 production increases in muscle and promotes lipophagy in the liver via an AMPK-dependent pathway [28]. Interestingly, in a rat model of NAFLD, induction of a microRNA, miR-212, decreases the levels of FGF-21 mRNA and protein in liver, and exercise reverses this effect by inhibiting the expression of this microRNA [29]. Metabolic disorders can block the hepatic release of FGF-21 after exercise as has happened in diabetic patients [27]. In fact, the release of FGF-21 is lower in obese patients with hyperinsulinemia compared with healthy subjects [30]. However, this fact must be confirmed by more studies since a recent study showed high levels of FGF-21 levels in NAFLD patients and a decrease after 12 weeks of resistance exercise, in a response attributed to the prevention of the progression of NAFLD [31]. To date, the effect of chronic exercise on levels of FGF-21 is not clear and more research must be performed in order to determine its importance in the inter-organ cross talk [16].

    2.1.2. Fetuin A

    Fetuin A is a 64-KDa glycoprotein secreted by both, liver and adipose tissue. This hepatokine inhibits insulin signaling and is directly correlated with adiposity in NAFLD patients [32]. Interestingly, the relationship of this hepatokine with the improvement of NAFLD in exercise is not clear since after six months of aerobic exercise and weight loss program, the levels of this hepatokine increased at the same time that glucose metabolism improved [33]. However, a direct relationship between increase in fetuin A and VO2max in these patients was found, indicating a relationship of this kepatokine with the improvement of muscle function [33]. On the other hand, a short-term exercise program in obese adults clinically diagnosed with NAFLD produced a decrease in circulating fetuin A levels, along with improved insulin resistance and muscle glucose uptake [34]. The same effect was found in old adults after a supervised exercise training for 12 weeks [35]. Again, the relationship of this hepatokine with physiological improvement in NAFLD patients must be established with more controlled studies.

    2.1.3. Activin and Follistatin (FST)

    Activin E is a member of the TGF-β family [36], considered recently as a hepatokine that is elevated in liver and serum in humans with obesity and NAFLD [37], although many of its functions have been associated with the regulation of adipose tissue [38]. Activin has been associated with the increase of steatosis in liver through the induction of the insulin response [39]; and activation of activin receptors by myostatin and activin also favors inflammation and fibrosis [40]. Interestingly, activin A has also been associated with the increase of atrophy in skeletal muscle linked to NAFLD [41][42].

    On the other hand, follistatin (FST) is a member of the TGF-β superfamily that acts as antagonist against myostatin and activin A through binding to their receptors and affects the regulation of skeletal muscle growth [43]. This hepatokine is essential for the normal development of muscle since its absence produces insufficient muscle development and skeletal abnormalities in mice [16]. On the other hand, high levels of FST block myostatin/activin action producing antiatrophic effects in muscle. Although FST is also produced in muscle, exercise seems to increase the release of liver FST to plasma [44] in a response attributed to the increase in the glucagon-to-insulin ratio during exercise [27]. In relationship to chronic exercise, resistance training increases the circulating FST in plasma of elderly overweight women [45]. Although recent studies point to the role of FST in NAFLD and other metabolic disorders, little is known about its long-term adaptation to regular exercise and further experiments must be performed in order to understand its relationship with metabolic modifications induced by exercise.

    2.1.4. Retinol-Binding Protein 4

    Considered also as an adipocytokine, RBP4, has been associated with insulin resistance in skeletal muscle. In humans, clinical cross-sectional studies have shown conflicting results indicating a negative correlation between RBP4 levels and insulin sensitivity [46]. In a NAFLD rat model, a 7-week treadmill exercise program was able to reduce RBP4 levels in plasma, although this decrease was associated with fat tissue [47].

    In humans, plasma RBP4 levels are high in T2DM, obesity, metabolic syndrome and cardiovascular disease and interventions such as diet, exercise, antidiabetic drugs and hypolipidemic agents decrease their levels [48]. In children, RBP4 levels were high in obese individuals but changes in lifestyle based on exercise were able to decrease these levels at the same time as reducing inflammatory factors in plasma [49].

    2.1.5. Angiopoietin-Like Protein 4

    Angiopoietin-like protein 4 (ANGPL4) is a glycoprotein of approximately 45–65 kDa secreted by liver and adipose tissue [50]. Although its relevance in metabolic disorders of this hepatokine is not clear, it is well established that the protein regulates lipid metabolism by stimulating lipolysis in adipocytes [51] and inhibiting lipoprotein lipase activity [52]. Studies performed in humans have demonstrated that systemic ANGPLT4 increases during fasting and is secreted from the liver after exercise [53].

    The relationship of ANGPL4 with insulin resistance improvement after exercise is not clear. It has been reported that, in obese people, a 6-month program of exercise and diet did not change ANGPTL4 serum levels indicating that other factors contribute to the insulin sensitivity improvement found after this program [52]. However, other studies have shown increased levels of ANGPTL4 after fasting, chronic CR and endurance exercise in a response associated with the increase of plasma free fatty acids levels [50]. The same result was found after a 12-week exercise program or a hypocaloric diet in obese patients indicating a similar response to both exercise and diet [54].

    2.1.6. Selenoprotein P

    Selenoprotein P (SeP) is a glycoprotein that can be released by liver and adipose tissue and has been shown to contribute to insulin resistance associated with NAFLD [55]. The effects of exercise on this marker are scarce but recent studies indicate that controlled and forced exercise programs reduce the levels of circulating SeP in NAFLD patients [56].

    In general, most of the studies performed in NAFLD patients indicate that exercise partially restores the level of hepatokines to those found in healthy patients. However, some studies introduce some discrepancies that must be resolved in order to clearly determine the relationship of these mediators to the progression of the disease and to the regulation introduced by exercise and/or diet.

    2.2. Myokines

    Acting as a massive endocrine organ, contracting muscle secretes a number of substances known as myokines [57]. To date some of the most well-known are interleukin (IL)-6, IL-10, IL-15, irisin, myostatin, brain derived neurotrophic factor (BDNF), β-amino-isobutyric acid, meteorin-like, leukemia inhibitory factor (LIF); when secreted, they are acidic and rich in cysteine (SARC) [58]. We will focus on the myokines that have shown a direct influence on the physiology of the liver and on their relationship with NAFLD.

    2.2.1. Follistatin-Like 1 and Apelin

    Follistin-like 1 (FSTL1) is considered an adipokine or myokine that has been related to insulin resistance in obese and diabetic patients, producing a pro-inflammatory response [59], although other studies have indicated its cardioprotective effect against ischemic injury [60] and it has been shown that FSTL1 levels are reduced in diabetes patients [61]. Apelin has also been associated with adipose tissue but recently it has also been considered as myokine upregulated after exercise and its release has been associated with decrease of fat levels and improvement of cardiovascular capacity [62].

    FSTL1 [63] and apelin [62] are expressed in myotubes and released after acute exercise. Both have a favorable effect on energy metabolism and rat studies have demonstrated that acute endurance exercise produces significant increases in plasma just after exercise without affecting tissue levels [64]. In humans, acute sprint interval training consisting of four 30-s all-out cycling efforts with 4-min rest periods also produced significant increases in plasma of both myokines [65]. Their role in NAFLD patients has not been studied in depth but we can speculate that these myokines can have an important effect on the reduction of fat and on the improvement of liver activity.

    2.2.2. FNDC5 and Irisin

    Irisin is a PGC-1α-induced myokine product of the cleavage of the fibronectin type III domain-containing protein 5 (FNDC5) [66]. Irisin is secreted by contracting skeletal muscle and has been associated with health benefits via changes in metabolism of white adipose tissue [67].

    Clinical studies have demonstrated that FNDC5 is essential for maintaining metabolic homeostasis and its dysregulation leads to imbalance of systemic metabolism [68]. Independently of its function as precursor or irisin, FNDC5 has been recently shown as relevant for the regulation of diverse upstream and downstream signaling pathways involved in metabolic syndrome [68]. FNDC5 is increased in fatty liver in both mice and humans without affecting plasma levels or irisin [69]. Downregulation of FNDC5 expression resulted in the increase of steatosis and in insulin resistance and higher apoptosis of primary hepatocytes to TNF-α. Probably, the high expression of FNDC5 in hepatocytes in NAFLD can be the consequence of a protective response against steatogenesis through the local release of irisin, or through the activation of downstream signaling molecules that regulate physiological modifications in response to accumulation of fat [68][69].

    Circulating irisin levels in patients with hepatic steatosis in comparison with controls are confusing. Some studies have shown that irisin levels are lower in obese, NAFLD and NASH patients in comparison with lean controls [70]. Low levels of serum irisin have been also reported in NAFLD, T2DM and NAFLD + T2DM patients in comparison with controls [71], and more recently a significant decrease of plasma irisin together with the adipokines omentin and vaspin have been reported in NAFLD and alcoholic cirrhotic patients [72]. However, other studies have shown that plasma irisin levels are high in NAFLD patients in comparison with controls [73] and the most recent study has shown that plasma of patients with NAFLD contains higher levels of irisin, in direct relationship with the IHL content [74]; further, in HIV patients without diabetes, higher irisin levels were associated with insulin resistance, NAFLD and subclinical atherosclerosis [75]. To add more confusion, another study did not find differences in the levels of irisin between controls and NAFLD patients [76]. It seems clear that the relationship of NAFLD and plasma irisin levels must be resolved in order to understand the physiological relevance of this myokine to NAFLD progression.

    Although the mechanism is not clear, physical activity produces the release of irisin into plasma in an intensity-dependent manner [77]. The release of irisin can be gender dependent affecting more women than men [78]. Interestingly, irisin release after exercise can impair the progression of hepatic fibrosis by regulating the activation, proliferation, migration, contractility and inflammatory cytokine release from hepatic stellate cells [79]. In a recent study, Zhang et al., [80] demonstrated that irisin protects steatotic liver after ischemia/reperfusion in mice through inhibiting ROS production and improving mitochondrial dysfunction. This effect was associated with the binding of irisin to integrin receptors in hepatic cells and activation of kindlin-2, a member of the 4.1-ezrin-ridixin-moesin (FERM) domain family of proteins that regulates many biological functions after interacting with the cytoplasmic tails of β-integrin subunits [81]. However, the role of irisin-dependent kindlin-2 activation is controversial since this protein is considered a biomarker for poor prognosis of liver cancer patients [81] and its deficiency attenuates mouse liver fibrosis and hepatic stellate cells activation [82]. Again, further research is needed in order to understand the putative hepatoprotective effect of irisin in exercised patients.

    2.2.3. Interleukin-6 (IL-6)

    IL-6 is a well-known cytokine associated with liver disease that increases when NAFLD progresses to NASH [83]. It seems that IL-6 can be involved in the inhibition of hepatic autophagy induced by exhaustive physical exercise since IL-6 null mice show reduced levels of markers of autophagy in the liver [84]. However, the role of IL-6 in the exercise effect on NAFLD patients is puzzling, since their release, together with the levels of other cytokines, has been considered a positive effect, inducing anti-inflammatory responses and improving fat metabolism in the liver [85]. In any case, it seems clear that exercise induces the release of IL-6 from muscle. Plasma IL-6 increases exponentially during exercise depending on intensity, duration, muscle mass and endurance capacity [86][87][88]. Voluntary and electrical muscle contractions 19 min twice a week increased IL-6 levels in NAFLD patients in comparison with controls, improving insulin resistance and hepatic steatosis [89].

    The entry is from 10.3390/nu12113472

    References

    1. Rinella, M.E. Nonalcoholic Fatty Liver Disease. JAMA 2015, 313, 2263–2273.
    2. Divella, R.; Mazzocca, A.; Daniele, A.; Sabbà, C.; Paradiso, A. Obesity, Nonalcoholic Fatty Liver Disease and Adipocytokines Network in Promotion of Cancer. Int. J. Biol. Sci. 2019, 15, 610–616.
    3. Sarwar, R.; Pierce, N.; Koppe, S. Obesity and Nonalcoholic Fatty Liver Disease: Current Perspectives. Diabetes Metab. Syndr. 2018, 11, 533–542.
    4. Dyson, J.; Day, C. Treatment of Non-Alcoholic Fatty Liver Disease. Dig. Dis. 2014, 32, 597–604.
    5. Kontogianni, M.D.; Tileli, N.; Margariti, A.; Georgoulis, M.; Deutsch, M.; Tiniakos, D.; Fragopoulou, E.; Zafiropoulou, R.; Manios, Y.; Papatheodoridis, G. Adherence to the Mediterranean Diet Is Associated with the Severity of Non-Alcoholic Fatty Liver Disease. Clin. Nutr. 2014, 33, 678–683.
    6. Koppe, S.W. Obesity and the Liver: Nonalcoholic Fatty Liver Disease. Transl. Res. 2014, 164, 312–322.
    7. Çolak, Y.; Tuncer, I.; Şenateş, E.; Ozturk, O.; Doganay, L.; Yilmaz, Y. Nonalcoholic Fatty Liver Disease: A Nutritional Approach. Metab. Syndr. Relat. Disord. 2012, 10, 161–166.
    8. Zelber-Sagi, S.; Nitzan-Kaluski, D.; Goldsmith, R.; Webb, M.; Blendis, L.; Halpern, Z.; Oren, R. Long Term Nutritional Intake and the Risk for Non-Alcoholic Fatty Liver Disease (NAFLD): A Population Based Study. J. Hepatol. 2007, 47, 711–717.
    9. Ouyang, X.; Cirillo, P.; Sautin, Y.; McCall, S.; Bruchette, J.L.; Diehl, A.M.; Johnson, R.J.; Abdelmalek, M.F. Fructose Consumption as a Risk Factor for Non-Alcoholic Fatty Liver Disease. J. Hepatol. 2008, 48, 993–999.
    10. Patel, N.S.; Doycheva, I.; Peterson, M.R.; Hooker, J.; Kisselva, T.; Schnabl, B.; Seki, E.; Sirlin, C.B.; Loomba, R. Effect of Weight Loss on Magnetic Resonance Imaging Estimation of Liver Fat and Volume in Patients with Nonalcoholic Steatohepatitis. Clin. Gastroenterol. Hepatol. 2014, 13, 561–568.e1.
    11. Stefan, N.; Häring, H.-U.; Schulze, M.B. Metabolically Healthy Obesity: The Low-Hanging Fruit in Obesity Treatment? Lancet Diabetes Endocrinol. 2018, 6, 249–258.
    12. De Cabo, R.; Mattson, M.P. Effects of Intermittent Fasting on Health, Aging, and Disease. N. Engl. J. Med. 2019, 381, 2541–2551.
    13. Di Francesco, A.; Di Germanio, C.; Bernier, M.; De Cabo, R. A Time to Fast. Science 2018, 362, 770–775.
    14. Thoma, C.; Day, C.P.; Trenell, M.I. Lifestyle Interventions for the Treatment of Non-Alcoholic Fatty Liver Disease in Adults: A Systematic Review. J. Hepatol. 2012, 56, 255–266.
    15. Sheka, A.C.; Adeyi, O.; Thompson, J.; Hameed, B.; Crawford, P.A.; Ikramuddin, S. Nonalcoholic Steatohepatitis. JAMA 2020, 323, 1175–1183.
    16. Ennequin, G.; Sirvent, P.; Whitham, M. Role of Exercise-Induced Hepatokines in Metabolic Disorders. Am. J. Physiol. Metab. 2019, 317, E11–E24.
    17. Severinsen, M.C.K.; Pedersen, B.K. Muscle–Organ Crosstalk: The Emerging Roles of Myokines. Endocr. Rev. 2020, 41, 594–609.
    18. Weigert, C.; Hoene, M.; Plomgaard, P. Hepatokines—A Novel Group of Exercise Factors. Pflügers Arch. Eur. J. Physiol. 2018, 471, 383–396.
    19. Meex, R.C.R.; Watt, M.J. Hepatokines: Linking Nonalcoholic Fatty Liver Disease and Insulin Resistance. Nat. Rev. Endocrinol. 2017, 13, 509–520.
    20. Ke, Y.; Xu, C.; Lin, J.; Li, Y. Role of Hepatokines in Non-Alcoholic Fatty Liver Disease. J. Transl. Intern. Med. 2019, 7, 143–148.
    21. Watt, M.J.; Miotto, P.M.; De Nardo, W.; Montgomery, M.K. The Liver as an Endocrine Organ—Linking NAFLD and Insulin Resistance. Endocr. Rev. 2019, 40, 1367–1393.
    22. Nishimura, T.; Nakatake, Y.; Konishi, M.; Itoh, N. Identification of a Novel FGF, FGF-21, Preferentially Expressed in the Liver. Biochim. Biophys. Acta 2000, 1492, 203–206.
    23. Badman, M.K.; Koester, A.; Flier, J.S.; Kharitonenkov, A.; Maratos-Flier, E. Fibroblast Growth Factor 21-Deficient Mice Demonstrate Impaired Adaptation to Ketosis. Endocrinology 2009, 150, 4931–4940.
    24. Zarei, M.; Barroso, E.; Palomer, X.; Dai, J.; Rada, P.; Quesada-López, T.; Escolà-Gil, J.C.; Cedó, L.; Zali, M.R.; Molaei, M.; et al. Hepatic Regulation of VLDL Receptor by PPARβ/δ and FGF21 Modulates Non-Alcoholic Fatty Liver Disease. Mol. Metab. 2018, 8, 117–131.
    25. Zheng, Q.; Martin, R.C.; Shi, X.; Pandit, H.; Yu, Y.; Liu, X.; Guo, W.; Tan, M.; Bai, O.; Meng, X.; et al. Lack of FGF21 Promotes NASH-HCC Transition via Hepatocyte-TLR4-IL-17A Signaling. Theranostics 2020, 10, 9923–9936.
    26. Izumiya, Y.; Bina, H.A.; Ouchi, N.; Akasaki, Y.; Kharitonenkov, A.; Walsh, K. FGF21 is an Akt-Regulated Myokine. FEBS Lett. 2008, 582, 3805–3810.
    27. Hansen, J.S.; Pedersen, B.K.; Xu, G.; Lehmann, R.; Weigert, C.; Plomgaard, P. Exercise-Induced Secretion of FGF21 and Follistatin Are Blocked by Pancreatic Clamp and Impaired in Type 2 Diabetes. J. Clin. Endocrinol. Metab. 2016, 101, 2816–2825.
    28. Gao, Y.; Zhang, W.; Zeng, L.-Q.; Bai, H.; Li, J.; Zhou, J.; Zhou, G.-Y.; Fang, C.-W.; Wang, F.; Qin, X.-J. Exercise and Dietary Intervention Ameliorate High-Fat Diet-Induced NAFLD and Liver Aging by Inducing Lipophagy. Redox Biol. 2020, 36, 101635.
    29. Xiao, J.; Bei, Y.; Liu, J.; Dimitrova-Shumkovska, J.; Kuang, D.; Zhou, Q.; Li, J.; Yang, Y.; Xiang, Y.; Wang, F.; et al. miR-212 Downregulation Contributes to the Protective Effect of Exercise Against Non-Alcoholic Fatty Liver via Targeting FGF-21. J. Cell. Mol. Med. 2016, 20, 204–216.
    30. Slusher, A.L.; Whitehurst, M.; Zoeller, R.F.; Mock, J.; Maharaj, M.; Huang, C.-J. Attenuated Fibroblast Growth Factor 21 Response to Acute Aerobic Exercise in Obese Individuals. Nutr. Metab. Cardiovasc. Dis. 2015, 25, 839–845.
    31. Takahashi, A.; Abe, K.; Fujita, M.; Hayashi, M.; Okai, K.; Ohira, H. Simple Resistance Exercise Decreases Cytokeratin 18 and Fibroblast Growth Factor 21 Levels in Patients with Nonalcoholic Fatty Liver Disease. Medicine 2020, 99, e20399.
    32. Trepanowski, J.F.; Mey, J.T.; Varady, K.A. Fetuin-A: A Novel Link Between Obesity and Related Complications. Int. J. Obes. 2014, 39, 734–741.
    33. Blumenthal, J.B.; Gitterman, A.; Ryan, A.S.; Prior, S.J. Effects of Exercise Training and Weight Loss on Plasma Fetuin-A Levels and Insulin Sensitivity in Overweight Older Men. J. Diabetes Res. 2017, 2017, 1–7.
    34. Malin, S.K.; Mulya, A.; Fealy, C.E.; Haus, J.M.; Pagadala, M.R.; Scelsi, A.R.; Huang, H.; Flask, C.A.; McCullough, A.J.; Kirwan, J.P. Fetuin-A Is Linked to Improved Glucose Tolerance After Short-Term Exercise Training in Nonalcoholic Fatty Liver Disease. J. Appl. Physiol. 2013, 115, 988–994.
    35. Malin, S.K.; Del Rincon, J.P.; Huang, H.; Kirwan, J.P. Exercise-Induced Lowering of Fetuin-A May Increase Hepatic Insulin Sensitivity. Med. Sci. Sports Exerc. 2014, 46, 2085–2090.
    36. Yndestad, A.; Haukeland, J.W.; Dahl, T.B.; Bjøro, K.; Gladhaug, I.P.; Berge, C.; Damås, J.K.; Haaland, T.; Løberg, E.M.; Linnestad, P.; et al. A Complex Role of Activin A in Non-Alcoholic Fatty Liver Disease. Am. J. Gastroenterol. 2009, 104, 2196–2205.
    37. Hashimoto, O.; Funaba, M.; Sekiyama, K.; Doi, S.; Shindo, D.; Satoh, R.; Itoi, H.; Oiwa, H.; Morita, M.; Suzuki, C.; et al. Activin E Controls Energy Homeostasis in Both Brown and White Adipose Tissues as a Hepatokine. Cell Rep. 2018, 25, 1193–1203.
    38. Ungerleider, N.A.; Bonomi, L.M.; Brown, M.L.; Schneyer, A. Increased Activin Bioavailability Enhances Hepatic Insulin Sensitivity While Inducing Hepatic Steatosis in Male Mice. Endocrinology 2013, 154, 2025–2033.
    39. Polyzos, S.A.; Kountouras, J.; Anastasilakis, A.D.; Triantafyllou, G.A.; Mantzoros, C.S. Activin A and Follistatin in Patients with Nonalcoholic Fatty Liver Disease. Metabolism 2016, 65, 1550–1558.
    40. Chen, J.L.; Walton, K.L.; Qian, H.; Colgan, T.D.; Hagg, A.; Watt, M.J.; Harrison, C.A.; Gregorevic, P. Differential Effects of IL6 and Activin A in the Development of Cancer-Associated Cachexia. Cancer Res. 2016, 76, 5372–5382.
    41. Loumaye, A.; De Barsy, M.; Nachit, M.; Lause, P.; Frateur, L.; Van Maanen, A.; Tréfois, P.; Gruson, D.; Thissen, J.-P. Role of Activin A and Myostatin in Human Cancer Cachexia. J. Clin. Endocrinol. Metab. 2015, 100, 2030–2038.
    42. Loumaye, A.; De Barsy, M.; Nachit, M.; Lause, P.; Frateur, L.; Van Maanen, A.; Tréfois, P.; Gruson, D.; Thissen, J.-P. Role of Activin A and Myostatin in Human Cancer Cachexia. J. Clin. Endocrinol. Metab. 2015, 100, 2030–2038.
    43. Patel, K. Follistatin. Int. J. Biochem. Cell Biol. 1998, 30, 1087–1093.
    44. Hansen, J.; Brandt, C.; Nielsen, A.R.; Hojman, P.; Whitham, M.; Febbraio, M.A.; Pedersen, B.K.; Plomgaard, P. Exercise Induces a Marked Increase in Plasma Follistatin: Evidence That Follistatin Is a Contraction-Induced Hepatokine. Endocrinology 2011, 152, 164–171.
    45. Hofmann, M.; Schober-Halper, B.; Oesen, S.; Franzke, B.; Tschan, H.; Bachl, N.; Strasser, E.-M.; Quittan, M.; Wagner, K.-H.; Wessner, B. Effects of Elastic Band Resistance Training and Nutritional Supplementation on Muscle Quality and Circulating Muscle Growth and Degradation Factors of Institutionalized Elderly Women: The Vienna Active Ageing Study (VAAS). Eur. J. Appl. Physiol. 2016, 116, 885–897.
    46. Takebayashi, K.; Aso, Y.; Inukai, T. Role of Retinol-Binding Protein 4 in the Pathogenesis of Type 2 Diabetes. Expert Rev. Endocrinol. Metab. 2008, 3, 161–173.
    47. Mansouri, M.; Nikooie, R.; Keshtkar, A.; Larijani, B.; Omidfar, K. Effect of Endurance Training on Retinol-Binding Protein 4 Gene Expression and Its Protein Level in Adipose Tissue and the Liver in Diabetic Rats Induced by a High-Fat Diet and Streptozotocin. J. Diabetes Investig. 2014, 5, 484–491.
    48. Christou, G.; Tselepis, A.; Kiortsis, D. The Metabolic Role of Retinol Binding Protein 4: An Update. Horm. Metab. Res. 2011, 44, 6–14.
    49. Balagopal, P.; Graham, T.E.; Kahn, B.B.; Altomare, A.; Funanage, V.; George, D. Reduction of Elevated Serum Retinol Binding Protein in Obese Children by Lifestyle Intervention: Association with Subclinical Inflammation. J. Clin. Endocrinol. Metab. 2007, 92, 1971–1974.
    50. Kersten, S.; Lichtenstein, L.; Steenbergen, E.; Mudde, K.; Hendriks, H.F.; Hesselink, M.K.; Schrauwen, P.; Müller, M. Caloric Restriction and Exercise Increase Plasma ANGPTL4 Levels in Humans via Elevated Free Fatty Acids. Arterioscler. Thromb. Vasc. Biol. 2009, 29, 969–974.
    51. Gray, N.E.; Lam, L.N.; Yang, K.; Zhou, A.Y.; Koliwad, S.; Wang, J.-C. Angiopoietin-Like 4 (Angptl4) Protein Is a Physiological Mediator of Intracellular Lipolysis in Murine Adipocytes. J. Biol. Chem. 2017, 292, 16135.
    52. Ingerslev, B.; Hansen, J.S.; Hoffmann, C.; Clemmesen, J.O.; Secher, N.H.; Scheler, M.; De Angelis, M.H.; Häring, H.U.; Pedersen, B.K.; Weigert, C.; et al. Angiopoietin-Like Protein 4 Is an Exercise-Induced Hepatokine in Humans, Regulated by Glucagon and cAMP. Mol. Metab. 2017, 6, 1286–1295.
    53. Li, G.; Zhang, H.; Ryan, A.S. Skeletal Muscle Angiopoietin-Like Protein 4 and Glucose Metabolism in Older Adults after Exercise and Weight Loss. Metabolites 2020, 10, 354.
    54. Cullberg, K.B.; Christiansen, T.; Paulsen, S.K.; Bruun, J.M.; Pedersen, S.B.; Richelsen, B. Effect of Weight Loss and Exercise on Angiogenic Factors in the Circulation and in Adipose Tissue in Obese Subjects. Obesity 2013, 21, 454–460.
    55. Choi, H.Y.; Hwang, S.Y.; Lee, C.H.; Hong, H.C.; Yang, S.J.; Yoo, H.J.; Seo, J.A.; Kim, S.G.; Kim, N.H.; Baik, S.H.; et al. Increased Selenoprotein P Levels in Subjects with Visceral Obesity and Nonalcoholic Fatty Liver Disease. Diabetes Metab. J. 2013, 37, 63–71.
    56. Iwanaga, S.; Hashida, R.; Takano, Y.; Bekki, M.; Nakano, D.; Omoto, M.; Nago, T.; Kawaguchi, T.; Matsuse, H.; Torimura, T.; et al. Hybrid Training System Improves Insulin Resistance in Patients with Nonalcoholic Fatty Liver Disease: A Randomized Controlled Pilot Study. Tohoku J. Exp. Med. 2020, 252, 23–32.
    57. Pedersen, B.K. Muscles and Their Myokines. J. Exp. Biol. 2010, 214, 337–346.
    58. Huh, J.Y. The Role of Exercise-Induced Myokines in Regulating Metabolism. Arch. Pharmacal Res. 2017, 41, 14–29.
    59. Fan, N.; Sun, H.; Wang, Y.; Wang, Y.; Zhang, L.; Xia, Z.; Peng, L.; Hou, Y.; Shen, W.; Liu, R.; et al. Follistatin-Like 1: A Potential Mediator of Inflammation in Obesity. Mediat. Inflamm. 2013, 2013, 1–12.
    60. Xi, Y.; Gong, D.-W.; Tian, Z. FSTL1 as a Potential Mediator of Exercise-Induced Cardioprotection in Post-Myocardial Infarction Rats. Sci. Rep. 2016, 6, 32424.
    61. Park, K.; Ahn, C.W.; Park, J.S.; Kim, Y.; Nam, J.S. Circulating Myokine Levels in Different Stages of Glucose Intolerance. Medicine 2020, 99, e19235.
    62. Bessepatin, A.; Montastier, E.; Vinel, C.; Castanlaurell, I.; Louche, K.; Dray, C.; Daviaud, D.; Mir, L.M.; Marques, M.-A.; Thalamas, C.; et al. Effect of Endurance Training on Skeletal Muscle Myokine Expression in Obese Men: Identification of Apelin as a Novel Myokine. Int. J. Obes. 2014, 38, 707–713.
    63. Görgens, S.W.; Raschke, S.; Holven, K.B.; Jensen, J.; Eckardt, K.; Eckel, J. Regulation of Follistatin-Like Protein 1 Expression and Secretion in Primary Human Skeletal Muscle Cells. Arch. Physiol. Biochem. 2013, 119, 75–80.
    64. Kon, M.; Tanimura, Y.; Yoshizato, H. Effects of Acute Endurance Exercise on Follistatin-Like 1 and Apelin in the Circulation and Metabolic Organs in Rats. Arch. Physiol. Biochem. 2020, 1–5.
    65. Kon, M.; Ebi, Y.; Nakagaki, K. Effects of Acute Sprint Interval Exercise on Follistatin-Like 1 and Apelin Secretions. Arch. Physiol. Biochem. 2019, 1–5.
    66. Bostroem, P.; Wu, J.; Jedrychowski, M.P.; Korde, A.; Ye, L.; Lo, J.C.; Rasbach, K.A.; Bostroem, E.A.; Choi, J.H.; Long, J.Z.; et al. A PGC1-α- Dependent Myokine That Drives Brown-Fat-Like Development of White Fat and Thermogenesis. Nature 2012, 481, 463–468.
    67. Kurdiova, T.; Balaz, M.; Vician, M.; Maderova, D.; Vlcek, M.; Valkovic, L.; Srbecky, M.; Imrich, R.; Kyselovicova, O.; Belan, V.; et al. Effects of Obesity, Diabetes and Exercise onfndc5gene Expression and Irisin Release in Human Skeletal Muscle and Adipose Tissue: In Vivo and in Vitro studies. J. Physiol. 2014, 592, 1091–1107.
    68. Cao, R.Y.; Zheng, H.; Redfearn, D.; Yang, J. FNDC5: A Novel Player in Metabolism and Metabolic Syndrome. Biochimie 2019, 158, 111–116.
    69. Canivet, C.M.; Bonnafous, S.; Rousseau, D.; LeClere, P.S.; Lacas-Gervais, S.; Patouraux, S.; Sans, A.; Luci, C.; Bailly-Maitre, B.; Iannelli, A.; et al. Hepatic FNDC5 is a Potential Local Protective Factor Against Non-Alcoholic Fatty Liver. Biochim. Biophys. Acta 2020, 1866, 165705.
    70. Polyzos, S.A.; Kountouras, J.; Anastasilakis, A.D.; Geladari, E.V.; Mantzoros, C.S. Irisin in Patients with Nonalcoholic Fatty Liver Disease. Metabolism 2014, 63, 207–217.
    71. Shanaki, M.; Moradi, N.; Emamgholipour, S.; Fadaei, R.; Poustchi, H. Lower Circulating Irisin Is Associated with Nonalcoholic Fatty Liver Disease and Type 2 Diabetes. Diabetes Metab. Syndr. 2017, 11, S467–S472.
    72. Waluga, M.; Kukla, M.; Kotulski, R.; Zorniak, M.; Boryczka, G.; Kajor, M.; Lekstan, A.; Olczyk, P.; Waluga, E. Omentin, Vaspin and Irisin in Chronic Liver Diseases. J. Physiol. Pharmacol. 2019, 70, 277–285.
    73. Choi, E.S.; Kim, M.K.; Song, M.K.; Kim, J.M.; Kim, E.S.; Chung, W.J.; Park, K.S.; Cho, K.B.; Hwang, J.S.; Jang, B.K. Association between Serum Irisin Levels and Non-Alcoholic Fatty Liver Disease in Health Screen Examinees. PLoS ONE 2014, 9, e110680.
    74. Monserrat-Mesquida, M.; Quetglas-Llabrés, M.; Abbate, M.; Montemayor, S.; Mascaró, C.M.; Casares, M.; Tejada, S.; Abete, I.; Zulet, M.A.; Tur, J.A.; et al. Oxidative Stress and Pro-Inflammatory Status in Patients with Non-Alcoholic Fatty Liver Disease. Antioxidants 2020, 9, 759.
    75. Moreno-Pérez, O.; Reyes-Garcia, R.; Muñoz-Torres, M.; Merino, E.; Boix, V.; Reus, S.; Giner, L.; Alfayate, R.; García-Fontana, B.; Sánchez-Payá, J.; et al. High Irisin Levels in Nondiabetic HIV-Infected Males Are Associated with Insulin Resistance, Nonalcoholic Fatty Liver Disease, and Subclinical Atherosclerosis. Clin. Endocrinol. 2018, 89, 414–423.
    76. Polyzos, S.A.; Kountouras, J.; Anastasilakis, A.D.; Margouta, A.; Mantzoros, C.S. Association Between Circulating Irisin and Homocysteine in Patients with Nonalcoholic Fatty Liver Disease. Endocrine 2014, 49, 560–562.
    77. De La Torre-Saldaña, V.A.; Gómez-Sámano, M.Á.; Gómez-Pérez, F.J.; Rosas-Saucedo, J.; León-Suárez, A.; Grajales-Gómez, M.; Oseguera-Moguel, J.; Vega-Beyhart, A.; Cuevas-Ramos, D. Fasting Insulin and Alanine Amino Transferase, but not FGF21, Were Independent Parameters Related with Irisin Increment after Intensive Aerobic Exercising. Rev. Investig. Clin. 2019, 71, 133–140.
    78. Wiecek, M.; Szymura, J.; Maciejczyk, M.; Kantorowicz, M.; Szygula, Z. Acute Anaerobic Exercise Affects the Secretion of Asprosin, Irisin, and Other Cytokines–A Comparison Between Sexes. Front. Physiol. 2018, 9, 9.
    79. Dong, H.N.; Park, S.Y.; Le, C.T.; Choi, D.-H.; Cho, E.-H. Irisin Regulates the Functions of Hepatic Stellate Cells. Endocrinol. Metab. 2020, 35, 647–655.
    80. Zhang, J.; Ren, Y.; Bi, J.; Wang, M.; Zhang, L.; Wang, T.; Wei, S.; Mou, X.; Lv, Y.; Wu, R. Involvement of Kindlin-2 in Irisin’s Protection Against Ischaemia Reperfusion-Induced Liver Injury in High-Fat Diet-Fed Mice. J. Cell. Mol. Med. 2020.
    81. Ge, Y.; Liu, N.; Jia, W.-D.; Li, J.-S.; Ma, J.-L.; Yu, J.-H.; Xu, G. Kindlin-2: A Novel Prognostic Biomarker for Patients with Hepatocellular Carcinoma. Pathol. Res. Pract. 2015, 211, 198–202.
    82. Yu, J.; Hu, Y.; Gao, Y.; Li, Q.; Zeng, Z.; Li, Y.; Chen, H. Kindlin-2 Regulates Hepatic Stellate Cells Activation and Liver Fibrogenesis. Cell Death Discov. 2018, 4, 34.
    83. Hadinia, A.; Doustimotlagh, A.H.; Goodarzi, H.R.; Arya, A.; Jafarinia, M. Circulating Levels of Pro-inflammatory Cytokines in Patients with Nonalcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis. Iran. J. Immunol. 2019, 16, 327–333.
    84. Pinto, A.P.; Da Rocha, A.L.; Cabrera, E.M.; Marafon, B.B.; Kohama, E.B.; Rovina, R.L.; Simabuco, F.M.; Junior, C.R.B.; De Moura, L.P.; Pauli, J.R.; et al. Role of Interleukin-6 in Inhibiting Hepatic Autophagy Markers in Exercised Mice. Cytokine 2020, 130, 155085.
    85. Monteiro, P.A.; Prado, W.L.D.; Tenório, T.R.D.S.; Tomaz, L.M.; St-Pierre, D.H.; Lira, F. Immunometabolic Changes in Hepatocytes Arising from Obesity and the Practice of Physical Exercise. Curr. Pharm. Des. 2018, 24, 3200–3209.
    86. Febbraio, M.A.; Pedersen, B.K. Muscle-Derived Interleukin-6: Mechanisms for Activation and Possible Biological Roles. FASEB J. 2002, 16, 1335–1347.
    87. Pedersen, B.K.; Steensberg, A.; Fischer, C.; Keller, C.; Keller, P.; Plomgaard, P.; Febbraio, M.; Saltin, B. Searching for the Exercise Factor: Is IL-6 a Candidate? J. Muscle Res. Cell Motil. 2003, 24, 113–119.
    88. Pedersen, B.K.; Febbraio, M. Muscle-Derived Interleukin-6—A Possible Link Between Skeletal Muscle, Adipose Tissue, Liver, and Brain. Brain Behav. Immun. 2005, 19, 371–376.
    89. Kawaguchi, T.; Shiba, N.; Maeda, T.; Matsugaki, T.; Takano, Y.; Itou, M.; Sakata, M.; Taniguchi, E.; Nagata, K.; Sata, M. Hybrid Training of Voluntary and Electrical Muscle Contractions Reduces Steatosis, Insulin Resistance, and IL-6 Levels in Patients with NAFLD: A Pilot Study. J. Gastroenterol. 2011, 46, 746–757.
    90. Kawaguchi, T.; Shiba, N.; Maeda, T.; Matsugaki, T.; Takano, Y.; Itou, M.; Sakata, M.; Taniguchi, E.; Nagata, K.; Sata, M. Hybrid Training of Voluntary and Electrical Muscle Contractions Reduces Steatosis, Insulin Resistance, and IL-6 Levels in Patients with NAFLD: A Pilot Study. J. Gastroenterol. 2011, 46, 746–757.
    More
    1. Please check and comment entries here.