Volume 11, Issue 4 (12-2023)
Jorjani Biomed J 2023, 11(4): 3-7 |
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Shahriari R, sheikhani shahin H, Moghaddasi M, Jowhari A. The the role of eight weeks of combined high-intensity interval training in modulating intrahepatic FNDC5 protein and irisin levels in male rats with non-alcoholic steatohepatitis. Jorjani Biomed J 2023; 11 (4) :3-7
URL: http://goums.ac.ir/jorjanijournal/article-1-988-en.html
URL: http://goums.ac.ir/jorjanijournal/article-1-988-en.html
1- Department of Sports Sciences, Zand Institution of Higher Education, Shiraz, Iran
2- Department of Sports Sciences, Zand Institution of Higher Education, Shiraz, Iran ,hsheikhani@yahoo.com
3- Department of Sports Sciences, Shiraz Branch, Islamic Azad University, Shiraz, Iran
4- Department of Sports Sciences, Faculty of Educational Sciences and Psychology, Shiraz University, Shiraz, Iran
2- Department of Sports Sciences, Zand Institution of Higher Education, Shiraz, Iran ,
3- Department of Sports Sciences, Shiraz Branch, Islamic Azad University, Shiraz, Iran
4- Department of Sports Sciences, Faculty of Educational Sciences and Psychology, Shiraz University, Shiraz, Iran
Keywords: High-intensity interval training, Non-alcoholic steatohepatitis, High-fat diet, FNDC5 protein, rat, Lipid metabolism, FNDC5
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Introduction
Nonalcoholic steatohepatitis (NASH) affects up to 30% of people with NAFLD and is characterized by inflammation, necrosis of the liver, severe insulin resistance, and cardiometabolic dysfunction. With disease progression mainly due to insulin resistance, NASH affects up to 37% of people with type 2 diabetes (T2DM). NASH is strongly associated with cardiovascular disease morbidity and mortality and the risk of liver cirrhosis. It increases hepatocellular carcinoma and a wide range of extrahepatic malignancies (1). Management of NASH focuses on lifestyle modification regarding diet quality and increased physical activity to reduce body mass by 7–10% (2).
Irisin originates from cleavage of the extracellular portion of fibronectin type III domain-containing protein 5 (FNDC5) and was first identified as a myokine regulated by exercise. By promoting white fat cell "browning" and thermogenesis, secreted irisin increases energy expenditure (3), which in turn can limit body weight gain and insulin resistance and plays an important role in diabetes and non-alcoholic fatty liver diseases (NAFLDs), including non-alcoholic steatohepatitis (NASH) (4,5). Furthermore, the relationship between systemic irisin levels and the development of NAFLDs and nonalcoholic steatohepatitis is still debated (6).
Even though adipose tissues and the liver also express and secrete irisin, it is difficult to estimate the relative contribution of muscle, liver, and adipose tissue to the secretion of circulating irisin. Furthermore, the relationship between systemic irisin levels and the development of NAFLDs and nonalcoholic steatohepatitis is still debated (7). Wrann et al. (2015) have shown that 32 days of voluntary exercise on a turning wheel in six-week-old male rats leads to an increase in the expression of the FNDC5 gene (7). Bonfante et al. (2017) showed that combined training maintained FNDC5/irisin levels and provided metabolic and fitness benefits in obese men (8). Also, Makiel et al. (2023) showed that combined exercise improved irisin performance, reduced insulin resistance, and reduced visceral fat mass in men with metabolic syndrome (9). There is evidence that exercise-induced FNDC5 triggers the effect of exercise through skeletal muscle on other organs, including visceral fat (10,11). Through irisin, FNDC5 can indirectly convert white fat into brown fat, and with this mechanism, reduce obesity and diabetes and improve NAFLD. Reisi et al. (2016) concluded that resistance exercise may improve body composition by increasing thermogenesis in white adipose tissue through irisin secretion (11).
As a result, it is possible that the levels of FNDC5 and exercise determine the amount of brown fat in the body. Therefore, there is a hypothesis that brown adipose tissue (BAT) can improve insulin sensitivity and cause weight loss (12). Bonfante et al. (2017) showed that higher levels of FNDC5/irisin in obese middle-aged men were associated with a better metabolic profile and lower risk of type 2 diabetes (12).
High-intensity interval training (HIIT) consists of periods of high-intensity exercise followed by periods of passive or active recovery (13). Emerging longitudinal evidence from small clinical trials suggests that HIIT produces comparable reductions in liver fat to traditional moderate-intensity continuous exercise (14). However, these studies did not include subjects with biopsy-proven NASH (15). Since water has a high-temperature transfer property and can cause the body temperature to decrease during sports activities and thus reduce the systemic inflammation of the body (16), it is likely that the increase in lipid metabolism and its related factors, including irisin, increases in combination with training in the land. Despite this, there is little research in this regard, and the minimum necessary amount of physical activity for developing physical health is still not completely clear (16). the present study investigated the effect of eight weeks of combined high-intensity interval training on intrahepatic FNDC5 protein and irisin in male rats with non-alcoholic steatohepatitis.
Methods
This research selected 40 male Sprague-Dawley rats (age: 8 weeks) with an average weight of 230 ± 20 grams. The rats were kept in the animal house of Shiraz University with an ambient temperature of 22-24°C, humidity of 45%, and a light-dark cycle of 12-12. The ethical principles of working with the animals in the study were considered per the Helsinki Declaration, and the code of ethics obtained was IR.SUMS.AEC.1402.017. The rats were divided into standard food (n=20) and high-fat diet (HFD) groups. HFD was given to rats in the form of emulsion by gavage method (10 ml/kg/day). The content of HFD consisted of 77% fat (corn oil and cholesterol powder), 14% protein (milk powder), and 9% carbohydrates (sucrose) (17). The healthy group was also gavage with the same amount of salt solution (saline) daily. After proving the induction of disease in rats, the high-fat diet group was randomly divided into control-patient (n=9), exercise-patient (n=9) and healthy group and control-healthy (n=9), group exercise-healthy (n = 9) were divided. The HFD of the patient groups continued until the end of the training period.
HIIT swimming workout:
In the first week of acclimatization, the rats swam alternately in the animal pool (diameter 160 cm and height 80 cm) with a water depth of 50 cm and an average temperature of 30±0.5°C for 20 minutes. In the second week of adaptation, to familiarize themselves with the type of interval training, they were taken out of the water several times after swimming for one minute by the resting plate and put back in the water (18). Forty-eight hours after the last familiarization session, the main exercise was performed for eight weeks, two days a week (Saturday and Wednesday), according to Table 1 (19).
HIIT on a treadmill:
Two weeks before the start of the study, the animals were acclimatized through a daily low-intensity running protocol for 20 minutes on a treadmill at a speed of 10 m/min. After the familiarization phase, the main exercise protocol, according to Table 2, was performed one day a week (Mondays) and for eight weeks (20,21).
Forty-eight hours after the last training session, rats were injected intraperitoneally with a combination of ketamine (30 to 50 mg/kg body weight) and xylazine (3 to 5 mg/kg body weight) and were anesthetized and dissected, and the liver tissue was harvested. To measure irisin proteins (β-Αctin (C4): sc-47778, Irisin (42-112) (Human, Rat, Mouse, Canine) - purified IgG antibody) catalog number G-067-17 and FNDC5 (β-Αctin (C4): sc-47778, Anti-FNDC5 antibody ab131390) was done through western blot technique.
Western Blot
In general, the steps of the western blot technique include tissue lysing, determination of protein concentration by Bradford, preparation of different concentrations of BSA to draw a standard curve, protein concentrations, water and sample buffer, sample preparation, and electrofuge on SDS gel. page, preparation of solutions, test method and making of lower and upper gel, electrophoresis on SDS page gel, western blot or immunoblotting, transfer step from gel to paper, blocking step, incubation step with primary antibody (β-Αctin (C4) : sc-47778, Irisin (42-112) (Human, Rat, Mouse, Canine) - purified IgG antibody) catalog number G-067-17 and (β-Αctin (C4): sc-47778, Anti-FNDC5 antibody ab131390) from abcam company, incubation step with secondary antibody (m-IgGκ ΒP-HRP: sc-516102, mouse αanti-rαββit IgG-HRP: sc-2357), detection step, film development step in the dark-room, method It was striping.
Data analysis
One-way variance was used to analyze the data, and if the differences were significant, Bonferroni's post hoc test was used to determine the exact location of the differences. The statistical analysis was carried out using the SPSS version 26 software, and the significance level was set at P<0.05.
Results
Results related to proof of disease and weight changes
Figure 1 shows the mean ± standard deviation of the weight changes of the healthy (n = 20) and high-fat diet (HFD) (n = 20) groups during eight weeks of high-fat diet induction. In order to prove the development of NASH disease, two rats were randomly sacrificed from the diseased (n=2) and healthy (n=2) groups. As an example, in Figure 2, the diseased liver and the healthy liver are demonstrated together for comparison. In Figure 3, the results of Oil red O staining of diseased and healthy liver tissue are compared and reported. Table 3 of patient samples 1 and 2 after eight weeks of feeding with a high-fat diet, steatosis and inflammation score, serum ALT and AST values, and liver histological analysis showed that the liver of rats was in the second stage of fibrosis. Based on the average weight of each group in the entire period of exercise intervention (Figure 4), it was found that between exercise-patient and exercise-healthy groups (P=0.038) and control-patient (P=0.027) and control-healthy (P=0.031) there was a significant difference in the seventh week. Therefore, the average weight of the exercise-patient group experienced a significant decrease compared to the control-patient group (P=0.027).
Western Blot results
In Table 4, descriptive data, including the mean, standard deviation, minimum, maximum, and the number of animals for each dependent variable in terms of experimental groups, are displayed.
In Figure 5, the results of the western blot bands for intrahepatic FNDC5 protein are reported for each group. As shown in Figure 6, based on the results of the one-way analysis of the variance test, there was no significant difference between the mean of FNDC5 (P=0.125). However, after examining the averages, it was found that the training-patient group had a non-significant decrease of 43.884% compared to the control-patient group (P=0.9).
In Figure 7, the results of the western blot bands for intrahepatic irisin protein are reported for each group. As shown in Figure 8, based on the results of one-way variance analysis, there is a significant difference between the irisin mean (P=0.007). According to Bonferroni's post hoc test, this difference was associated with a significant increase in the training-healthy group compared to the control-healthy (P=0.046) and control-patient (P=0.011) groups, and there was a significant increase in the training-patient group compared to the control-patient group (P=0.036).
Discussion
The present study aimed to investigate the effect of eight weeks of high-intensity interval training on intrahepatic FNDC5 and irisin protein in male rats with non-alcoholic steatohepatitis. The findings showed that there was a non-significant decrease in FNDC5 protein in the training-patient group compared to the control-patient group. Also, there was a significant increase in irisin protein in the training-patient group compared to the control-patient group and a significant increase in the training-healthy group compared to the control-patient group. Based on the results of recent research, it is worth mentioning the study conducted by Bastu et al. (2018). They found that after eight weeks of aerobic training, there was a significant increase in the irisin variable in the training group compared to the control group (22). Another relevant study is that of Dehghani et al. (2022). Following a period of resistance training in their research, these researchers found a significant increase in plasma irisin levels and no difference in FNDC5 levels in men aged 30 to 50 years compared to the control group (23). The study by Kurdiova et al. (2014) found that while muscle FNDC5 mRNA increased in pre-diabetic conditions, it did not increase in type 2 diabetes or advanced insulin resistance. They also found that FNDC5 in adipose tissue and irisin in plasma decreased in type 2 diabetes. Further, they stated in their research that circulating irisin was positively related to muscle mass, strength, and metabolism and negatively related to fasting blood sugar (24). First, it should be said that according to the previous findings and the current research findings, FNDC5 is the precursor of irisin, and their changes are expected to be aligned. However, in response to different conditions (either type of disease, type of intervention or type of subject) they showed different changes. The researchers simultaneously investigated the adaptations and changes of two proteins, FNDC5, and irisin, in liver tissue in response to a high-fat diet and high-intensity interval training interventions. Part of the research findings of Cordiva et al. (2014) were consistent with the findings of the present research. In the current research, combined high-intensity interval training did not have a significant effect on FNDC5 levels in the groups. Based on the findings of Kurdiova et al., FNDC5 may elicit varying responses to physical activity depending on the disease model and tissue being measured.
However, the findings of Kurdiova et al.'s research were partially inconsistent with the findings of the present study. In the present study, irisin increased significantly in the training groups compared to the control group, and this shows that the sports-induced adaptation increases the breakdown of inactive FNDC5 and turns it into active irisin. Also, the FNDC5/Irisin/UCP-1 signal increases and augments fat browning. As a result, it can be suggested that contrary to the results of Kurdiova et al., the findings of this research indicate that combined high-intensity interval training can have a potential effect on the browning of white fat in the liver and improve non-alcoholic steatohepatitis (NASH) (24).
There is evidence that irisin has a positive correlation with muscle mass and a negative correlation with fat mass (25). In this regard, in the present study, the weight of the training-patient group had a significant decrease compared to the control-patient group, wherein the weight loss was caused by the reduction of visceral fat in the training-patient group because both groups constantly used a 77% high-fat diet. This decrease in fat levels occurred while the intrahepatic irisin levels, as an indicator of blood serum irisin levels, increased significantly in the training-patient group compared to the control-patient. In a study by Jiang et al. (2021), mice overexpressed irisin had a slight weight loss compared to the control group. Muscle mass is the only predictor of serum irisin levels (26).
In the present study, the weight difference in the training-patient group was significantly lower compared to the control-patient rats. Therefore, it is likely that combined high-intensity interval training reduced fat and increased muscle mass in the training-patient group compared to the control-patient rats.
Short-term control of obesity through weight loss exercise may improve insulin resistance by increasing irisin levels, even in rats with a high-fat diet (22), as in the present research, in which rats in the patient groups (either control-patient or training-patient) were constantly using a high-fat diet.
Based on these results, it can be proposed that following high-intensity interval training, the rate of FNDC5 conversion to irisin increased, and subsequently, the activity of irisin increased.
Since irisin is an indicator of fat browning, it is possible that as irisin increases, the hepatic and visceral fat also decrease. Accordingly, in the present study, a significant decrease in the weight of the training-patient group compared to the control-patient group was observed.
Conclusion
Since irisin has a muscle source, it is possible that with weight loss in the training-patient group, the muscle volume increased following combined high-intensity interval training. Also, part of the increase in hepatic irisin can be attributed to the augmented release of muscle irisin and its positive feedback effect on the hepatic irisin increase in non-alcoholic steatohepatitis (NASH) disease. Nonetheless, further research is necessary to obtain conclusive results.
Acknowledgement
The authors express their sincere gratitude to all individuals who assisted in carrying out this research.
Funding sources
The researchers personally provided the financial support required for the current research.
Ethical statement
The ethical principles (Code of ethics) of the study were considered in accordance with the principles of working with laboratory animals approved by Shiraz University of Medical Sciences (IR.SUMS.AEC.1402.017).
Conflicts of interest
The writers of this piece want to clarify that they have no conflicts of interest.
Author contributions
All authors contributed to the present study.
Nonalcoholic steatohepatitis (NASH) affects up to 30% of people with NAFLD and is characterized by inflammation, necrosis of the liver, severe insulin resistance, and cardiometabolic dysfunction. With disease progression mainly due to insulin resistance, NASH affects up to 37% of people with type 2 diabetes (T2DM). NASH is strongly associated with cardiovascular disease morbidity and mortality and the risk of liver cirrhosis. It increases hepatocellular carcinoma and a wide range of extrahepatic malignancies (1). Management of NASH focuses on lifestyle modification regarding diet quality and increased physical activity to reduce body mass by 7–10% (2).
Irisin originates from cleavage of the extracellular portion of fibronectin type III domain-containing protein 5 (FNDC5) and was first identified as a myokine regulated by exercise. By promoting white fat cell "browning" and thermogenesis, secreted irisin increases energy expenditure (3), which in turn can limit body weight gain and insulin resistance and plays an important role in diabetes and non-alcoholic fatty liver diseases (NAFLDs), including non-alcoholic steatohepatitis (NASH) (4,5). Furthermore, the relationship between systemic irisin levels and the development of NAFLDs and nonalcoholic steatohepatitis is still debated (6).
Even though adipose tissues and the liver also express and secrete irisin, it is difficult to estimate the relative contribution of muscle, liver, and adipose tissue to the secretion of circulating irisin. Furthermore, the relationship between systemic irisin levels and the development of NAFLDs and nonalcoholic steatohepatitis is still debated (7). Wrann et al. (2015) have shown that 32 days of voluntary exercise on a turning wheel in six-week-old male rats leads to an increase in the expression of the FNDC5 gene (7). Bonfante et al. (2017) showed that combined training maintained FNDC5/irisin levels and provided metabolic and fitness benefits in obese men (8). Also, Makiel et al. (2023) showed that combined exercise improved irisin performance, reduced insulin resistance, and reduced visceral fat mass in men with metabolic syndrome (9). There is evidence that exercise-induced FNDC5 triggers the effect of exercise through skeletal muscle on other organs, including visceral fat (10,11). Through irisin, FNDC5 can indirectly convert white fat into brown fat, and with this mechanism, reduce obesity and diabetes and improve NAFLD. Reisi et al. (2016) concluded that resistance exercise may improve body composition by increasing thermogenesis in white adipose tissue through irisin secretion (11).
As a result, it is possible that the levels of FNDC5 and exercise determine the amount of brown fat in the body. Therefore, there is a hypothesis that brown adipose tissue (BAT) can improve insulin sensitivity and cause weight loss (12). Bonfante et al. (2017) showed that higher levels of FNDC5/irisin in obese middle-aged men were associated with a better metabolic profile and lower risk of type 2 diabetes (12).
High-intensity interval training (HIIT) consists of periods of high-intensity exercise followed by periods of passive or active recovery (13). Emerging longitudinal evidence from small clinical trials suggests that HIIT produces comparable reductions in liver fat to traditional moderate-intensity continuous exercise (14). However, these studies did not include subjects with biopsy-proven NASH (15). Since water has a high-temperature transfer property and can cause the body temperature to decrease during sports activities and thus reduce the systemic inflammation of the body (16), it is likely that the increase in lipid metabolism and its related factors, including irisin, increases in combination with training in the land. Despite this, there is little research in this regard, and the minimum necessary amount of physical activity for developing physical health is still not completely clear (16). the present study investigated the effect of eight weeks of combined high-intensity interval training on intrahepatic FNDC5 protein and irisin in male rats with non-alcoholic steatohepatitis.
Methods
This research selected 40 male Sprague-Dawley rats (age: 8 weeks) with an average weight of 230 ± 20 grams. The rats were kept in the animal house of Shiraz University with an ambient temperature of 22-24°C, humidity of 45%, and a light-dark cycle of 12-12. The ethical principles of working with the animals in the study were considered per the Helsinki Declaration, and the code of ethics obtained was IR.SUMS.AEC.1402.017. The rats were divided into standard food (n=20) and high-fat diet (HFD) groups. HFD was given to rats in the form of emulsion by gavage method (10 ml/kg/day). The content of HFD consisted of 77% fat (corn oil and cholesterol powder), 14% protein (milk powder), and 9% carbohydrates (sucrose) (17). The healthy group was also gavage with the same amount of salt solution (saline) daily. After proving the induction of disease in rats, the high-fat diet group was randomly divided into control-patient (n=9), exercise-patient (n=9) and healthy group and control-healthy (n=9), group exercise-healthy (n = 9) were divided. The HFD of the patient groups continued until the end of the training period.
HIIT swimming workout:
In the first week of acclimatization, the rats swam alternately in the animal pool (diameter 160 cm and height 80 cm) with a water depth of 50 cm and an average temperature of 30±0.5°C for 20 minutes. In the second week of adaptation, to familiarize themselves with the type of interval training, they were taken out of the water several times after swimming for one minute by the resting plate and put back in the water (18). Forty-eight hours after the last familiarization session, the main exercise was performed for eight weeks, two days a week (Saturday and Wednesday), according to Table 1 (19).
|
Table 1. HIIT swimming workout protocol (Saturday and Wednesday)
 |
Two weeks before the start of the study, the animals were acclimatized through a daily low-intensity running protocol for 20 minutes on a treadmill at a speed of 10 m/min. After the familiarization phase, the main exercise protocol, according to Table 2, was performed one day a week (Mondays) and for eight weeks (20,21).
|
Table 2. Land training protocol
 |
Western Blot
In general, the steps of the western blot technique include tissue lysing, determination of protein concentration by Bradford, preparation of different concentrations of BSA to draw a standard curve, protein concentrations, water and sample buffer, sample preparation, and electrofuge on SDS gel. page, preparation of solutions, test method and making of lower and upper gel, electrophoresis on SDS page gel, western blot or immunoblotting, transfer step from gel to paper, blocking step, incubation step with primary antibody (β-Αctin (C4) : sc-47778, Irisin (42-112) (Human, Rat, Mouse, Canine) - purified IgG antibody) catalog number G-067-17 and (β-Αctin (C4): sc-47778, Anti-FNDC5 antibody ab131390) from abcam company, incubation step with secondary antibody (m-IgGκ ΒP-HRP: sc-516102, mouse αanti-rαββit IgG-HRP: sc-2357), detection step, film development step in the dark-room, method It was striping.
Data analysis
One-way variance was used to analyze the data, and if the differences were significant, Bonferroni's post hoc test was used to determine the exact location of the differences. The statistical analysis was carried out using the SPSS version 26 software, and the significance level was set at P<0.05.
Results
Results related to proof of disease and weight changes
Figure 1 shows the mean ± standard deviation of the weight changes of the healthy (n = 20) and high-fat diet (HFD) (n = 20) groups during eight weeks of high-fat diet induction. In order to prove the development of NASH disease, two rats were randomly sacrificed from the diseased (n=2) and healthy (n=2) groups. As an example, in Figure 2, the diseased liver and the healthy liver are demonstrated together for comparison. In Figure 3, the results of Oil red O staining of diseased and healthy liver tissue are compared and reported. Table 3 of patient samples 1 and 2 after eight weeks of feeding with a high-fat diet, steatosis and inflammation score, serum ALT and AST values, and liver histological analysis showed that the liver of rats was in the second stage of fibrosis. Based on the average weight of each group in the entire period of exercise intervention (Figure 4), it was found that between exercise-patient and exercise-healthy groups (P=0.038) and control-patient (P=0.027) and control-healthy (P=0.031) there was a significant difference in the seventh week. Therefore, the average weight of the exercise-patient group experienced a significant decrease compared to the control-patient group (P=0.027).
|
Table 3. Results of tissue and blood tests to show non-alcoholic steatohepatitis (NASH).
 |
Western Blot results
In Table 4, descriptive data, including the mean, standard deviation, minimum, maximum, and the number of animals for each dependent variable in terms of experimental groups, are displayed.
|
Table 4. Descriptive statistics of the research variables
 |
In Figure 7, the results of the western blot bands for intrahepatic irisin protein are reported for each group. As shown in Figure 8, based on the results of one-way variance analysis, there is a significant difference between the irisin mean (P=0.007). According to Bonferroni's post hoc test, this difference was associated with a significant increase in the training-healthy group compared to the control-healthy (P=0.046) and control-patient (P=0.011) groups, and there was a significant increase in the training-patient group compared to the control-patient group (P=0.036).
Discussion
The present study aimed to investigate the effect of eight weeks of high-intensity interval training on intrahepatic FNDC5 and irisin protein in male rats with non-alcoholic steatohepatitis. The findings showed that there was a non-significant decrease in FNDC5 protein in the training-patient group compared to the control-patient group. Also, there was a significant increase in irisin protein in the training-patient group compared to the control-patient group and a significant increase in the training-healthy group compared to the control-patient group. Based on the results of recent research, it is worth mentioning the study conducted by Bastu et al. (2018). They found that after eight weeks of aerobic training, there was a significant increase in the irisin variable in the training group compared to the control group (22). Another relevant study is that of Dehghani et al. (2022). Following a period of resistance training in their research, these researchers found a significant increase in plasma irisin levels and no difference in FNDC5 levels in men aged 30 to 50 years compared to the control group (23). The study by Kurdiova et al. (2014) found that while muscle FNDC5 mRNA increased in pre-diabetic conditions, it did not increase in type 2 diabetes or advanced insulin resistance. They also found that FNDC5 in adipose tissue and irisin in plasma decreased in type 2 diabetes. Further, they stated in their research that circulating irisin was positively related to muscle mass, strength, and metabolism and negatively related to fasting blood sugar (24). First, it should be said that according to the previous findings and the current research findings, FNDC5 is the precursor of irisin, and their changes are expected to be aligned. However, in response to different conditions (either type of disease, type of intervention or type of subject) they showed different changes. The researchers simultaneously investigated the adaptations and changes of two proteins, FNDC5, and irisin, in liver tissue in response to a high-fat diet and high-intensity interval training interventions. Part of the research findings of Cordiva et al. (2014) were consistent with the findings of the present research. In the current research, combined high-intensity interval training did not have a significant effect on FNDC5 levels in the groups. Based on the findings of Kurdiova et al., FNDC5 may elicit varying responses to physical activity depending on the disease model and tissue being measured.
However, the findings of Kurdiova et al.'s research were partially inconsistent with the findings of the present study. In the present study, irisin increased significantly in the training groups compared to the control group, and this shows that the sports-induced adaptation increases the breakdown of inactive FNDC5 and turns it into active irisin. Also, the FNDC5/Irisin/UCP-1 signal increases and augments fat browning. As a result, it can be suggested that contrary to the results of Kurdiova et al., the findings of this research indicate that combined high-intensity interval training can have a potential effect on the browning of white fat in the liver and improve non-alcoholic steatohepatitis (NASH) (24).
There is evidence that irisin has a positive correlation with muscle mass and a negative correlation with fat mass (25). In this regard, in the present study, the weight of the training-patient group had a significant decrease compared to the control-patient group, wherein the weight loss was caused by the reduction of visceral fat in the training-patient group because both groups constantly used a 77% high-fat diet. This decrease in fat levels occurred while the intrahepatic irisin levels, as an indicator of blood serum irisin levels, increased significantly in the training-patient group compared to the control-patient. In a study by Jiang et al. (2021), mice overexpressed irisin had a slight weight loss compared to the control group. Muscle mass is the only predictor of serum irisin levels (26).
In the present study, the weight difference in the training-patient group was significantly lower compared to the control-patient rats. Therefore, it is likely that combined high-intensity interval training reduced fat and increased muscle mass in the training-patient group compared to the control-patient rats.
Short-term control of obesity through weight loss exercise may improve insulin resistance by increasing irisin levels, even in rats with a high-fat diet (22), as in the present research, in which rats in the patient groups (either control-patient or training-patient) were constantly using a high-fat diet.
Based on these results, it can be proposed that following high-intensity interval training, the rate of FNDC5 conversion to irisin increased, and subsequently, the activity of irisin increased.
Since irisin is an indicator of fat browning, it is possible that as irisin increases, the hepatic and visceral fat also decrease. Accordingly, in the present study, a significant decrease in the weight of the training-patient group compared to the control-patient group was observed.
Conclusion
Since irisin has a muscle source, it is possible that with weight loss in the training-patient group, the muscle volume increased following combined high-intensity interval training. Also, part of the increase in hepatic irisin can be attributed to the augmented release of muscle irisin and its positive feedback effect on the hepatic irisin increase in non-alcoholic steatohepatitis (NASH) disease. Nonetheless, further research is necessary to obtain conclusive results.
Acknowledgement
The authors express their sincere gratitude to all individuals who assisted in carrying out this research.
Funding sources
The researchers personally provided the financial support required for the current research.
Ethical statement
The ethical principles (Code of ethics) of the study were considered in accordance with the principles of working with laboratory animals approved by Shiraz University of Medical Sciences (IR.SUMS.AEC.1402.017).
Conflicts of interest
The writers of this piece want to clarify that they have no conflicts of interest.
Author contributions
All authors contributed to the present study.
Type of Article: Original article |
Subject:
Health
Received: 2023/07/24 | Accepted: 2023/12/21 | Published: 2023/12/29
Received: 2023/07/24 | Accepted: 2023/12/21 | Published: 2023/12/29
References
1. Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology (Baltimore, Md). 2023;77(4):1335-47. [View at Publisher] [DOI] [PMID] [Google Scholar]
2. Quek J, Chan KE, Wong ZY, Tan C, Tan B, Lim WH, et al. Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2023;8(1):20-30. [View at Publisher] [DOI] [PMID] [Google Scholar]
3. Kim H, Wrann CD, Jedrychowski M, Vidoni S, Kitase Y, Nagano K, et al. Irisin mediates effects on bone and fat via αV integrin receptors. Cell. 2018;175(7):1756-68. [View at Publisher] [DOI] [PMID] [Google Scholar]
4. Bhanji RA, Narayanan P, Allen AM, Malhi H, Watt KD. Sarcopenia in hiding: the risk and consequence of underestimating muscle dysfunction in nonalcoholic steatohepatitis. Hepatology. 2017;66(6):2055-65. [View at Publisher] [DOI] [PMID] [Google Scholar]
5. Leal LG, Lopes MA, Batista Jr ML. Physical exercise-induced myokines and muscle-adipose tissue crosstalk: a review of current knowledge and the implications for health and metabolic diseases. Front Physiol. 2018;9:1307. [View at Publisher] [DOI] [PMID] [Google Scholar]
6. Kosmalski M, Drzewoski J, Szymczak-Pajor I, Zieleniak A, Mikołajczyk-Solińska M, Kasznicki J, et al. Irisin Is Related to Non-Alcoholic Fatty Liver Disease (NAFLD). Biomedicines. 2022;10(9):2253. [View at Publisher] [DOI] [PMID] [Google Scholar]
7. Wrann CD. FNDC5/Irisin-their role in the nervous system and as a mediator for beneficial effects of exercise on the brain. Brain Plast. 2015;1(1):55-61. [View at Publisher] [DOI] [PMID] [Google Scholar]
8. Bonfante ILP, Chacon-Mikahil MPT, Brunelli DT, Gáspari AF, Duft RG, Lopes WA, et al. Combined training, FNDC5/irisin levels and metabolic markers in obese men: A randomised controlled trial. Eur J Sport Sci. 2017;17(5):629-37. [View at Publisher] [DOI] [PMID] [Google Scholar]
9. Makiel K, Suder A, Targosz A, Maciejczyk M, Haim A. Effect of Exercise Interventions on Irisin and Interleukin-6 Concentrations and Indicators of Carbohydrate Metabolism in Males with Metabolic Syndrome. J Clin Med. 2023;12(1):369. [View at Publisher] [DOI] [PMID] [Google Scholar]
10. Panati K, Suneetha Y, Narala V. Irisin/FNDC5-An updated review. Eur Rev Med Pharmacol Sci. 2016;20(4):689-97. [view at publisher] [Google Scholar]
11. Reisi J, Ghaedi K, Rajabi H, Marandi SM. Can Resistance Exercise Alter Irisin Levels and Expression Profiles of FNDC5 and UCP1 in Rats? Asian J Sports Med. 2016;7(4):e35205. [view at publisher] [DOI:10.5812/asjsm.35205] [PMID] [Google Scholar]
12. Bonfante ILP, Chacon-Mikahil MPT, Brunelli DT, Gáspari AF, Duft RG, Oliveira AG, et al. Obese with higher FNDC5/Irisin levels have a better metabolic profile, lower lipopolysaccharide levels and type 2 diabetes risk. Arch Endocrinol Metab. 2017;61(6):524-33. [view at publisher] [DOI] [PMID] [Google Scholar]
13. Edwards JJ, Griffiths M, Deenmamode AH, O'Driscoll JM. High-Intensity Interval Training and Cardiometabolic Health in the General Population: A Systematic Review and Meta-Analysis of Randomised Controlled Trials. Sports Medicine. 2023;53(9):1753-63. [view at publisher] [DOI] [PMID] [Google Scholar]
14. Keating SE, Croci I, Wallen MP, Cox ER, Thuzar M, Pham U, et al. High-Intensity Interval Training is Safe, Feasible and Efficacious in Nonalcoholic Steatohepatitis: A Randomized Controlled Trial. Dig Dis Sci. 2023;68(5):2123-39. [view at publisher] [DOI] [PMID] [Google Scholar]
15. Snipe RM, Costa RJ. Does the temperature of water ingested during exertional-heat stress influence gastrointestinal injury, symptoms, and systemic inflammatory profile? J Sci Med Sport. 2018;21(8):771-6. [view at publisher] [DOI] [PMID] [Google Scholar]
16. Salagre D, Chayah M, Molina-Carballo A, Oliveras-López M-J, Munoz-Hoyos A, Navarro-Alarcón M, et al. Melatonin induces fat browning by transdifferentiation of white adipocytes and de novo differentiation of mesenchymal stem cells. Food Funct. 2022;13(6):3760-75. [view at publisher] [DOI] [PMID] [Google Scholar]
17. Zou Y, Li J, Lu C, Wang J, Ge J, Huang Y, et al. High-fat emulsion-induced rat model of nonalcoholic steatohepatitis. Life sciences. 2006;79(11):1100-7. [view at publisher] [DOI] [PMID] [Google Scholar]
18. Farzanegi P, habibian m, alinejad h. The Combined Effect of Regular Aerobic Exercise with Garlic Extract on Renal Apoptosis Regulatory Factors in Aged rats with Chronic Kidney Disease. J Arak Uni Med Sci. 2016;19(3):62-70. [view at publisher] [Google Scholar]
19. Ramos-Filho D, Chicaybam G, de-Souza-Ferreira E, Guerra Martinez C, Kurtenbach E, Casimiro-Lopes G, et al. High intensity interval training (HIIT) induces specific changes in respiration and electron leakage in the mitochondria of different rat skeletal muscles. PloS One. 2015;10(6):e0131766. [view at publisher] [DOI] [PMID] [Google Scholar]
20. Dudley GA, Abraham WM, Terjung RL. Influence of exercise intensity and duration on biochemical adaptations in skeletal muscle. Journal of applied physiology. 1982;53(4):844-50. [view at publisher] [DOI] [PMID] [Google Scholar]
21. Shepherd RE, Gollnick PD. Oxygen uptake of rats at different work intensities. Pflugers Arch. 1976;362(3):219-22. [view at publisher] [DOI] [PMID] [Google Scholar]
22. Bastu E, Zeybek U, Gurel Gurevin E, Yüksel Ozgor B, Celik F, Okumus N, et al. Effects of Irisin and Exercise on Metabolic Parameters and Reproductive Hormone Levels in High-Fat Diet-Induced Obese Female Mice. Reprod Sci. 2018;25(2):281-91. [view at publisher] [DOI] [PMID] [Google Scholar]
23. Dehghani K, Mogharnasi M, Saghebjoo M, Sarir H, Malekaneh M. The Effect of Eight Weeks of Circuit Resistance Training and Spirulina Supplementation on Plasma Levels of Irisin and Some Body Composition in Overweight and Obese Men. Armaghane Danesh. 2020;25(3):332-45. [view at publisher] [DOI] [Google Scholar]
24. Kurdiova T, Balaz M, Vician M, Maderova D, Vlcek M, Valkovic L, et al. Effects of obesity, diabetes and exercise on Fndc5 gene expression and irisin release in human skeletal muscle and adipose tissue: in vivo and in vitro studies. The Journal of physiology. 2014;592(5):1091-107. [view at publisher] [DOI] [PMID] [Google Scholar]
25. Lagzdina R, Rumaka M, Gersone G, Tretjakovs P. Circulating irisin in healthy adults: Changes after acute exercise, correlation with body composition, and energy expenditure parameters in cross-sectional study. Medicina (Kaunas). 2020;56(6):274. [view at publisher] [DOI] [PMID] [Google Scholar]
26. Jiang S, Piao L, Ma EB, Ha H, Huh JY. Associations of circulating irisin with FNDC5 expression in fat and muscle in type 1 and type 2 diabetic mice. Biomolecules. 2021;11(2):322. [view at publisher] [DOI] [PMID] [Google Scholar]
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