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Irisin is a recently found myokine that aids obesity control and improves glucose homeostasis by acting on white adipose tissue cells and increases total energy consumption. The aim of this study was to evaluate serum irisin levels in patients with non-alcoholic fatty liver disease (NAFLD) and to compare these levels with those of normal controls....
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... serum irisin levels between the subjects with and without metabolic syndrome (45.5 6 19.3 vs. 47.9 6 32.5, p = 0.663). Even after the metabolic syndrome patients were excluded from the control group, serum irisin levels were still significantly higher in the NAFLD group than the control group (63.4 6 32.6 vs. 43.7 6 30.3, p , 0.001) The serum irisin level was not correlated with the quantity of exercise (r = 2 0.083, p = 0.254) (Table 4). Based on the weekly hours of exercise, we divided the subjects into three groups: the subjects in Group 1 (n = 195) did not exercise; those in Group 2 (n = 93) performed 1-h aerobic exercise weekly; and those in Group 3 (n = 67) performed . 1-h aerobic exercise weekly. Serum irisin levels showed a slight decrease as the level of exercise increased (Group 1, 48.6 6 24.9; Group 2, 46.6 6 41.9; and Group 3, 46.5 6 32.4; p = 0.055). In Group 1, there were 42 NAFLD subjects (21.5%) and 44 obese subjects (22.6%). In Group 2, there were 20 NAFLD subjects (21.5%) and 28 obese subjects (30.1%). In Group 3, there were 22 NAFLD subjects (32.8%) and 26 obese subjects (38.8%). Serum irisin levels tended to be higher in men than in women; however, there was no statistically significant difference between both sexes (52.9 6 32.7 vs. 45.8 6 30.9, p = 0.063). However, in both sex groups, there were significant differences between the sub-groups of NAFLD. In the male group, the serum irisin level was highest in the mild fatty liver group and lowest in the control group (49.5 6 38.2 vs. 62.9 6 23.6 vs. 53.5 6 18.7, p = 0.008). In the female group, the results were similar (41.3 6 26.9 vs. 71.6 6 45.1 vs. 60.5 6 24.3, p , 0.001) (Figure 3, Table S2). The correlation analysis revealed that the serum level of irisin correlated with that of insulin (r = 0.204, p , 0.001) and HOMA- IR (r = 0.205, p , 0.001). However, when we analyzed the correlation in the control group, the mild fatty liver group and the moderate-to-severe fatty liver group separately, the serum level of irisin did not significantly correlate with that of insulin (r = 0.100, p = 0.100 vs. r = 0.186, p = 0.210 vs. r = 2 0.145, p = 0.413) and HOMA-IR (r = 0.092, p = 0.130 vs. r = 0.172, p = 0.247 vs. r = 2 0.079, p = 0.657). The serum irisin level did not correlate with other parameters such as leptin, adiponectin, triglyceride, AST, and ALT levels (Table 4). Exercise is known to be beneficial in humans because it activates the transcriptional coactivator PGC1 a in muscles and stimulates the expression of Fndc5, a membrane protein that is cleaved and secreted as irisin [4]. Irisin was firstly recognized as a muscle- derived glycosylated polypeptide in 2012 by Bostrom et al. [4]. Irisin acts on white adipose cells, which stimulate UCP1 expression and brown fat progress [4]. Huh et al. reported that the amount of muscle is the primary predictor of the serum level of irisin. Serum irisin levels increase in response to acute exercise and decrease after surgically induced weight loss and with decrease in body mass [3]. Polyzos et al. published a recent study that evaluated serum irisin levels in patients with NAFLD and controls; serum irisin levels were significantly lower in obese controls and NAFLD patients than in lean controls. Their results indicate that irisin may be independently and positively associated with the presence of portal inflammation [7]. However, in the present study, serum irisin levels in the obese group were increased, which was consistent with the results of a previous study, but were inconsistent with those of another study on NAFLD subjects. In our analysis, serum irisin levels did not decrease in NAFLD patients; instead, the serum irisin level in the NAFLD group was higher than that of the control group. Furthermore, the serum irisin level was higher in the mild NAFLD group than the severe NAFLD group. Zhang et al. reported that serum irisin levels were low in obese adults with NAFLD and reduced gradually with the increase in intrahepatic triglyceride levels [10]. However, they did not evaluate serum irisin levels in normal controls. In that respect, our results also reveal a gradual decrease in the serum irisin level according to the severity of steatosis. Therefore, we hypothesized that the serum irisin level increases as a defense mechanism in the early stage of NAFLD and then, decreases with the progression of NAFLD. Although the mean BMI was higher in the NAFLD group, the serum irisin level was not different between the non-obese and obese groups. However, in the non-obese and obese groups, the serum irisin level was highest in the mild fatty liver group and lowest in the control group. Among the normal controls, the serum irisin level was lower in the obese group. In the mild fatty liver group and moderate-to-severe fatty liver group, there was no statistically significant difference in the serum irisin level between the obese and non-obese subjects; however, it tended to be lower in the obese group (Figure 2, Table S1). Consequently, we speculate that the increase of serum irisin in NAFLD patients is an independent process, not associated with BMI. Liu et al. reported that serum irisin was significantly lower in type 2 DM subjects than in non-diabetic controls [11]. However, in the present study, the number of patients with type 2 DM was too small to analyze the relationship between serum irisin level and type 2 DM. Park et al. reported that serum irisin levels were significantly higher in subjects with metabolic syndrome. They concluded that irisin is associated with metabolic syndrome independently from obesity. This association can be mediated not only by higher BMI or adiposity, but also by other mechanisms yet to be fully identified, including the direct effects on risk factors for metabolic syndrome [12]. However, although our data did not show a significant difference in serum irisin level between the metabolic syndrome group and normal control group, the number of subjects with metabolic syndrome was too low to reach a definite conclusion. Our results showed that the quantity of exercise was not positively correlated with serum irisin levels. In fact, some authors recently reported that the regulation of irisin by exercise has been shown only in small sized cohorts, and the timing of irisin increase after exercise was uncertain [13,14]. Kraemer et al. found temporarily elevated serum irisin levels in response to exercise, only during the first hour [15]. Hecksteden et al. failed to find an increase in serum irisin levels in healthy subjects after aerobic exercise [16]. In the present study, serum irisin levels showed a slight tendency to decrease with exercise; however, statistical significance was not reached. It is worth noting that there were more NAFLD patients and obese subjects in the exercise groups than in the non-exercise group. It is possible that the subjects who had NAFLD or were obese exercised more intensely than the healthy non-obese subjects before they were enrolled in the present study. Therefore, multiple complicated mechanisms may be involved in the relationship between serum irisin level and the quantity of exercise. In the present study, serum irisin levels tended to be higher in men than in women. However, the number of women (n = 261) included in our study was much higher than the number of men (n = 94). Therefore, we analyzed the characteristics of subjects per sex. The proportion of NAFLD patients in the male group was 40.4% (38/94) and that of the female group was 17.6% (46/261). This factor may have influenced the higher irisin level in the male group. Nevertheless, there were significant differences between the subgroups of NAFLD in both sex groups (Figure 3, Table S2). The serum irisin level is known to be lower in patients with fatty liver disease than in healthy individuals. However, recently published studies assert that serum irisin is not associated with BMI, age, and other biological parameters [14,16] and that it is somewhat inversely associated. Our results would support these findings. One hypothesis from Silja et al. is that human Fndc5 is a transcribed pseudo-gene that has lost the ability to be effectively translated into full-length Fndc5 protein. Therefore, unlike in mice, the role of irisin is lost in humans [17]. Although our study included a relatively large number of subjects, it has several limitations. Data regarding the amount of alcohol intake and the weekly hours of exercise were obtained by personal history taking; therefore, data may have been underes- timated or overestimated. We were unable to evaluate the intensity of exercise and the amount of muscle by imaging modality such as dual-energy X-ray absorptiometry or computed tomography. Finally, this study was limited by its cross-sectional design. In conclusion, although irisin is an interesting newly discovered protein, very little is known about it. It may be too premature to speculate an association between serum irisin levels and NAFLD. Our results showed that serum irisin levels were higher in NAFLD patients, which is not consistent with the results of previously published studies. Future studies will be required to ascertain the precise mechanisms regulating the effects of irisin on energy ...
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... irisin, leptin, and adiponectin levels with the ELISA kit (R&D, Minneapolis, MN, USA). We triple-checked these parameters and used mean values for analysis. We used the homeostasis model assessment-insulin resistance (HOMA-IR) value as the indicator of insulin resistance calculated using the following formula: fasting blood glucose (mg/dL) 6 insulin (mU/L)/(18 6 22.5) [9]. Furthermore, we examined liver function parameters and serum cholesterol levels, body mass index (BMI), abdominal circumference, thigh circumference, waist circumference, and hip circumference. We calculated BMI using the following formula: subject’s weight (kg)/height (m) 2 . We applied the term ‘‘obese group’’ to subjects whose BMI was . 25, and ‘‘non-obese group’’ to subjects whose BMI was , 25, according to the World Health Organiza- tion. Based on abdominal ultrasonography results, subjects were categorized as the control group, mild fatty liver group, and moderate-to-severe fatty liver group. We compared the demo- graphic characteristics, body measurements, body composition, and laboratory study results between the groups. The grade of steatosis was assessed by a single radiologist. The normal liver parenchyma has echogenicity equal to or slightly greater than that of the renal cortex. In fatty liver disease, the liver shows higher echogenicity than the renal cortex because of fatty infiltration. In mild fatty liver disease, only the echogenicity increases; in moderate fatty liver disease, the walls of the portal vein branches are indistinct; and in severe fatty liver disease, the diaphragmatic outline is indistinct [8]. We applied the term ‘‘mild fatty liver group’’ to subjects whose ultrasonographic finding was consistent with mild fatty liver, and ‘‘moderate-to-severe fatty liver group’’ to subjects whose ultrasonographic findings were consistent with moderate and severe fatty liver. Metabolic syndrome was diagnosed when three or more of the following criteria were met: 1) abdominal circumference $ 90 cm for men and $ 85 cm for women, 2) triglyceride (TG) level $ 150 mg/dL, 3) decreased high-density lipoprotein (HDL) at , 40 mg/dL for men and , 50 mg/dL for women, 4) blood pressure $ 130/85 mmHg, and 5) fasting blood sugar (FBS) level $ 150 mg/dL, or history of diabetes mellitus (DM)[9]. The study protocol was approved by the institutional review board of Keimyung University Dongsan Hospital (IRB Number 12-221). Statistical analyses were performed with SPSS software version 18.0 for Windows (IBM, NY, USA). Continuous variables are expressed as mean 6 SD. Categorical data were compared using the x 2 test. The Mann-Whitney U test and Kruskal-Wallis test were used to compare differences in continuous variables between each group. The correlation of irisin levels with other parameters was analyzed using Spearman correlation analysis. For all analyses, a p value # 0.05 was considered to indicate statistical significance. Comparative data of the study groups are presented in Table 1. The mean age of the NAFLD group was significantly higher than that of the control group ( p = 0.004), and the proportion of women was significantly higher in the control group ( p , 0.001). As expected, the mean BMI was significantly higher in the NAFLD group ( p , 0.001). Furthermore, there were statistically significant differences in FBS, insulin, HOMA, leptin, adiponectin, total cholesterol, TG, HDL, low-density lipoprotein (LDL), C-reactive protein (CRP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels between the two groups. The serum irisin level in the NAFLD group was significantly higher than that of the control group ( p , 0.001) (Table 1). According to the severity of steatosis, the serum irisin level was highest in the mild fatty liver group and lowest in the control group ( p , 0.001) (Figure 1, Table 2). Furthermore, other parameters such as serum levels of FBS, insulin, HOMA, leptin, total cholesterol, TG, LDL, CRP, AST, and ALT; systolic blood pressure; and diastolic systolic blood pressure were significantly higher in the moderate-to-severe fatty liver group than the mild fatty liver group and normal controls (Table 2). The adiponectin and HDL levels were significantly lower in the NAFLD group than the control group, especially in the moderate-to-severe fatty liver group ( p , 0.001). The waist and hip circumferences were higher in the NAFLD group, especially in the severe fatty liver group ( p , 0.001) (Table 2). Serum irisin levels (ng/ml) were not different between the non- obese and obese groups (48.4 6 34.2 vs. 45.8 6 22.9, p = 0.492) (Table 3). According to the severity of steatosis, the serum irisin level was lowest in normal controls and highest in the mild fatty liver group in the non-obese group (44.9 6 31.7 vs. 73.1 6 48.5 vs. 59.7 6 18.0, p , 0.001). In the obese group (52 healthy controls and 46 NAFLD patients), the results were similar (35.0 6 17.0 vs. 62.9 6 21.2 vs. 54.6 6 23.3, p , 0.001) (Figure 2, Table S1). According to the presence of obesity, in the control group, the serum irisin levels were significantly higher in the non-obese group than in the obese group (44.9 6 31.7 vs. 35.0 6 17.0, p = 0.030). On the other hand, in the NAFLD group including both the mild fatty liver group and the moderate-to-severe fatty liver group, the serum irisin level tended to be higher in the non-obese group than the obese group; however, the difference did not reach statistical significance (73.1 6 48.5 vs. 62.9 6 21.2, p = 0.365 and 59.7 6 18.0 vs. 54.6 6 23.3, p = 0.505) (Figure 2). Among the study subjects, there were 10 type 2 DM patients. When DM patients were excluded from the control group, serum irisin levels were still significantly higher in the NAFLD group than in the control group (63.4 6 32.6 vs. 43.0 6 29.9, p , 0.001). There were 37 study subjects with metabolic syndrome: 17 (6.3%) in the control group and 20 (23.8%) in the NAFLD group. There was no difference in serum irisin levels between the subjects with and without metabolic syndrome (45.5 6 19.3 vs. 47.9 6 32.5, p = 0.663). Even after the metabolic syndrome patients were excluded from the control group, serum irisin levels were still significantly higher in the NAFLD group than the control group (63.4 6 32.6 vs. 43.7 6 30.3, p , 0.001) The serum irisin level was not correlated with the quantity of exercise (r = 2 0.083, p = 0.254) (Table 4). Based on the weekly hours of exercise, we divided the subjects into three groups: the subjects in Group 1 (n = 195) did not exercise; those in Group 2 (n = 93) performed 1-h aerobic exercise weekly; and those in Group 3 (n = 67) performed . 1-h aerobic exercise weekly. Serum irisin levels showed a slight decrease as the level of exercise increased (Group 1, 48.6 6 24.9; Group 2, 46.6 6 41.9; and Group 3, 46.5 6 32.4; p = 0.055). In Group 1, there were 42 NAFLD subjects (21.5%) and 44 obese subjects (22.6%). In Group 2, there were 20 NAFLD subjects (21.5%) and 28 obese subjects (30.1%). In Group 3, there were 22 NAFLD subjects (32.8%) and 26 obese subjects (38.8%). Serum irisin levels tended to be higher in men than in women; however, there was no statistically significant difference between both sexes (52.9 6 32.7 vs. 45.8 6 30.9, p = 0.063). However, in both sex groups, there were significant differences between the sub-groups of NAFLD. In the male group, the serum irisin level was highest in the mild fatty liver group and lowest in the control group (49.5 6 38.2 vs. 62.9 6 23.6 vs. 53.5 6 18.7, p = 0.008). In the female group, the results were similar (41.3 6 26.9 vs. 71.6 6 45.1 vs. 60.5 6 24.3, p , 0.001) (Figure 3, Table S2). The correlation analysis revealed that the serum level of irisin correlated with that of insulin (r = 0.204, p , 0.001) and HOMA- IR (r = 0.205, p , 0.001). However, when we analyzed the correlation in the control group, the mild fatty liver group and the moderate-to-severe fatty liver group separately, the serum level of irisin did not significantly correlate with that of insulin (r = 0.100, p = 0.100 vs. r = 0.186, p = 0.210 vs. r = 2 0.145, p = 0.413) and HOMA-IR (r = 0.092, p = 0.130 vs. r = 0.172, p = 0.247 vs. r = 2 0.079, p = 0.657). The serum irisin level did not correlate with other parameters such as leptin, adiponectin, triglyceride, AST, and ALT levels (Table 4). Exercise is known to be beneficial in humans because it activates the transcriptional coactivator PGC1 a in muscles and stimulates the expression of Fndc5, a membrane protein that is cleaved and secreted as irisin [4]. Irisin was firstly recognized as a muscle- derived glycosylated polypeptide in 2012 by Bostrom et al. [4]. Irisin acts on white adipose cells, which stimulate UCP1 expression and brown fat progress [4]. Huh et al. reported that the amount of muscle is the primary predictor of the serum level of irisin. Serum irisin levels increase in response to acute exercise and decrease after surgically induced weight loss and with decrease in body mass [3]. Polyzos et al. published a recent study that evaluated serum irisin levels in patients with NAFLD and controls; serum irisin levels were significantly lower in obese controls and NAFLD patients than in lean controls. Their results indicate that irisin may be independently and positively associated with the presence of portal inflammation [7]. However, in the present study, serum irisin levels in the obese group were increased, which was consistent with the results of a previous study, but were inconsistent with those of another study on NAFLD subjects. In our analysis, serum irisin levels did not decrease in NAFLD patients; instead, the serum irisin level in the NAFLD group was higher than that of the control group. Furthermore, the serum irisin level was higher in the mild NAFLD group than the severe NAFLD group. Zhang et al. reported that serum irisin levels were low in obese adults with NAFLD and reduced gradually with the increase in ...
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... BMI using the following formula: subject’s weight (kg)/height (m) 2 . We applied the term ‘‘obese group’’ to subjects whose BMI was . 25, and ‘‘non-obese group’’ to subjects whose BMI was , 25, according to the World Health Organiza- tion. Based on abdominal ultrasonography results, subjects were categorized as the control group, mild fatty liver group, and moderate-to-severe fatty liver group. We compared the demo- graphic characteristics, body measurements, body composition, and laboratory study results between the groups. The grade of steatosis was assessed by a single radiologist. The normal liver parenchyma has echogenicity equal to or slightly greater than that of the renal cortex. In fatty liver disease, the liver shows higher echogenicity than the renal cortex because of fatty infiltration. In mild fatty liver disease, only the echogenicity increases; in moderate fatty liver disease, the walls of the portal vein branches are indistinct; and in severe fatty liver disease, the diaphragmatic outline is indistinct [8]. We applied the term ‘‘mild fatty liver group’’ to subjects whose ultrasonographic finding was consistent with mild fatty liver, and ‘‘moderate-to-severe fatty liver group’’ to subjects whose ultrasonographic findings were consistent with moderate and severe fatty liver. Metabolic syndrome was diagnosed when three or more of the following criteria were met: 1) abdominal circumference $ 90 cm for men and $ 85 cm for women, 2) triglyceride (TG) level $ 150 mg/dL, 3) decreased high-density lipoprotein (HDL) at , 40 mg/dL for men and , 50 mg/dL for women, 4) blood pressure $ 130/85 mmHg, and 5) fasting blood sugar (FBS) level $ 150 mg/dL, or history of diabetes mellitus (DM)[9]. The study protocol was approved by the institutional review board of Keimyung University Dongsan Hospital (IRB Number 12-221). Statistical analyses were performed with SPSS software version 18.0 for Windows (IBM, NY, USA). Continuous variables are expressed as mean 6 SD. Categorical data were compared using the x 2 test. The Mann-Whitney U test and Kruskal-Wallis test were used to compare differences in continuous variables between each group. The correlation of irisin levels with other parameters was analyzed using Spearman correlation analysis. For all analyses, a p value # 0.05 was considered to indicate statistical significance. Comparative data of the study groups are presented in Table 1. The mean age of the NAFLD group was significantly higher than that of the control group ( p = 0.004), and the proportion of women was significantly higher in the control group ( p , 0.001). As expected, the mean BMI was significantly higher in the NAFLD group ( p , 0.001). Furthermore, there were statistically significant differences in FBS, insulin, HOMA, leptin, adiponectin, total cholesterol, TG, HDL, low-density lipoprotein (LDL), C-reactive protein (CRP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels between the two groups. The serum irisin level in the NAFLD group was significantly higher than that of the control group ( p , 0.001) (Table 1). According to the severity of steatosis, the serum irisin level was highest in the mild fatty liver group and lowest in the control group ( p , 0.001) (Figure 1, Table 2). Furthermore, other parameters such as serum levels of FBS, insulin, HOMA, leptin, total cholesterol, TG, LDL, CRP, AST, and ALT; systolic blood pressure; and diastolic systolic blood pressure were significantly higher in the moderate-to-severe fatty liver group than the mild fatty liver group and normal controls (Table 2). The adiponectin and HDL levels were significantly lower in the NAFLD group than the control group, especially in the moderate-to-severe fatty liver group ( p , 0.001). The waist and hip circumferences were higher in the NAFLD group, especially in the severe fatty liver group ( p , 0.001) (Table 2). Serum irisin levels (ng/ml) were not different between the non- obese and obese groups (48.4 6 34.2 vs. 45.8 6 22.9, p = 0.492) (Table 3). According to the severity of steatosis, the serum irisin level was lowest in normal controls and highest in the mild fatty liver group in the non-obese group (44.9 6 31.7 vs. 73.1 6 48.5 vs. 59.7 6 18.0, p , 0.001). In the obese group (52 healthy controls and 46 NAFLD patients), the results were similar (35.0 6 17.0 vs. 62.9 6 21.2 vs. 54.6 6 23.3, p , 0.001) (Figure 2, Table S1). According to the presence of obesity, in the control group, the serum irisin levels were significantly higher in the non-obese group than in the obese group (44.9 6 31.7 vs. 35.0 6 17.0, p = 0.030). On the other hand, in the NAFLD group including both the mild fatty liver group and the moderate-to-severe fatty liver group, the serum irisin level tended to be higher in the non-obese group than the obese group; however, the difference did not reach statistical significance (73.1 6 48.5 vs. 62.9 6 21.2, p = 0.365 and 59.7 6 18.0 vs. 54.6 6 23.3, p = 0.505) (Figure 2). Among the study subjects, there were 10 type 2 DM patients. When DM patients were excluded from the control group, serum irisin levels were still significantly higher in the NAFLD group than in the control group (63.4 6 32.6 vs. 43.0 6 29.9, p , 0.001). There were 37 study subjects with metabolic syndrome: 17 (6.3%) in the control group and 20 (23.8%) in the NAFLD group. There was no difference in serum irisin levels between the subjects with and without metabolic syndrome (45.5 6 19.3 vs. 47.9 6 32.5, p = 0.663). Even after the metabolic syndrome patients were excluded from the control group, serum irisin levels were still significantly higher in the NAFLD group than the control group (63.4 6 32.6 vs. 43.7 6 30.3, p , 0.001) The serum irisin level was not correlated with the quantity of exercise (r = 2 0.083, p = 0.254) (Table 4). Based on the weekly hours of exercise, we divided the subjects into three groups: the subjects in Group 1 (n = 195) did not exercise; those in Group 2 (n = 93) performed 1-h aerobic exercise weekly; and those in Group 3 (n = 67) performed . 1-h aerobic exercise weekly. Serum irisin levels showed a slight decrease as the level of exercise increased (Group 1, 48.6 6 24.9; Group 2, 46.6 6 41.9; and Group 3, 46.5 6 32.4; p = 0.055). In Group 1, there were 42 NAFLD subjects (21.5%) and 44 obese subjects (22.6%). In Group 2, there were 20 NAFLD subjects (21.5%) and 28 obese subjects (30.1%). In Group 3, there were 22 NAFLD subjects (32.8%) and 26 obese subjects (38.8%). Serum irisin levels tended to be higher in men than in women; however, there was no statistically significant difference between both sexes (52.9 6 32.7 vs. 45.8 6 30.9, p = 0.063). However, in both sex groups, there were significant differences between the sub-groups of NAFLD. In the male group, the serum irisin level was highest in the mild fatty liver group and lowest in the control group (49.5 6 38.2 vs. 62.9 6 23.6 vs. 53.5 6 18.7, p = 0.008). In the female group, the results were similar (41.3 6 26.9 vs. 71.6 6 45.1 vs. 60.5 6 24.3, p , 0.001) (Figure 3, Table S2). The correlation analysis revealed that the serum level of irisin correlated with that of insulin (r = 0.204, p , 0.001) and HOMA- IR (r = 0.205, p , 0.001). However, when we analyzed the correlation in the control group, the mild fatty liver group and the moderate-to-severe fatty liver group separately, the serum level of irisin did not significantly correlate with that of insulin (r = 0.100, p = 0.100 vs. r = 0.186, p = 0.210 vs. r = 2 0.145, p = 0.413) and HOMA-IR (r = 0.092, p = 0.130 vs. r = 0.172, p = 0.247 vs. r = 2 0.079, p = 0.657). The serum irisin level did not correlate with other parameters such as leptin, adiponectin, triglyceride, AST, and ALT levels (Table 4). Exercise is known to be beneficial in humans because it activates the transcriptional coactivator PGC1 a in muscles and stimulates the expression of Fndc5, a membrane protein that is cleaved and secreted as irisin [4]. Irisin was firstly recognized as a muscle- derived glycosylated polypeptide in 2012 by Bostrom et al. [4]. Irisin acts on white adipose cells, which stimulate UCP1 expression and brown fat progress [4]. Huh et al. reported that the amount of muscle is the primary predictor of the serum level of irisin. Serum irisin levels increase in response to acute exercise and decrease after surgically induced weight loss and with decrease in body mass [3]. Polyzos et al. published a recent study that evaluated serum irisin levels in patients with NAFLD and controls; serum irisin levels were significantly lower in obese controls and NAFLD patients than in lean controls. Their results indicate that irisin may be independently and positively associated with the presence of portal inflammation [7]. However, in the present study, serum irisin levels in the obese group were increased, which was consistent with the results of a previous study, but were inconsistent with those of another study on NAFLD subjects. In our analysis, serum irisin levels did not decrease in NAFLD patients; instead, the serum irisin level in the NAFLD group was higher than that of the control group. Furthermore, the serum irisin level was higher in the mild NAFLD group than the severe NAFLD group. Zhang et al. reported that serum irisin levels were low in obese adults with NAFLD and reduced gradually with the increase in intrahepatic triglyceride levels [10]. However, they did not evaluate serum irisin levels in normal controls. In that respect, our results also reveal a gradual decrease in the serum irisin level according to the severity of steatosis. Therefore, we hypothesized that the serum irisin level increases as a defense mechanism in the early stage of NAFLD and then, decreases with the progression of NAFLD. Although the mean BMI was higher in the NAFLD group, the serum irisin level was not different between the non-obese and obese groups. However, in the non-obese and obese groups, the ...
Citations
... According to this report, they concluded that "irisin levels are gender-dependent and higher in women than in men". However, in a study by Choi et al., 15 It was found that serum irisin levels tend to be higher in men than women, but there was no statistically significant difference between both sexes (52.9 ± 32.7, 45.8 ± 30.9, p = 0.063). Therefore, it was concluded that there was no significant difference in serum and plasma samples in terms of gender irisin level without any disease. ...
Irisin is a myokine with 112 aminoacids and its level is regulated by peroxisome proliferator-activated receptor-γ coactivator1-α (PGC1-α). It is released into blood circulation from skeletal muscle tissue after a proteolytic cleavage of extracellular domain of Fibronectin type III domain-containing protein 5 (FNDC5), a type I integral membrain protein. Aprotinin is a polivalent serin protease inhibitor. It is added to sample solutions such as serum, plasma or tissue extracts in order to inhibit serine proteases found in the sample medium. So, degradation of the proteins to be measured can be prevented. These study has been made to get a preliminary information in order to see if any irisin loss could be seen in these samples which are frequently needed to be kept at -80°C for a long time. For this purpose, blood samples have been taken from 10 men and 10 women volunteers with ages between 25-40 and aprotinin has been added to the plasma and the serum samples and have been kept at -80°C for 3 months. At the end of 3 months, irisin levels of these samples with aprotinin and without aprotinin have been determined by ELISA. Statistical analysis of the results has shown an insignificant differance between the plasma samples with or without aprotinin (p=0.525) and a significant decrease between the serum samples with and without aprotinin (p=0.009). In conclusion, with the results of this study, no net decision could have been achieved to add aprotinin to the samples for irisin determination with ELISA in plasma and serum kept at -80°C for about 3 months.
... Many studies have indicated that the FNDC5/irisin system offers multiple advantages in metabolic diseases, such as an anti-inflammatory response in Alzheimer's disease (AD) by decreasing amyloid β-protein (Aβ) (Noda et al. 2018;Kim and Song 2018), antioxidant effects in type 2 diabetes (Zhu et al. 2015), and antiapoptotic effects in lipopolysaccharide-induced liver injury (Li et al. 2021). Moreover, some studies have shown that irisin is beneficial to ethanolinduced liver diseases, such as alcoholic fatty liver disease (AFLD), primary biliary cholangitis (PBC) and alcoholic cirrhosis (AC) (Choi et al. 2014;Waluga et al. 2019). However, most studies still focus on the effect of irisin on peripheral metabolic diseases caused by ethanol. ...
This study aims to investigate the effect of irisin on ethanol-induced behavioral deficits and explore the underlying mechanisms. A mouse model of ethanol addiction/withdrawal was constructed through chronic ethanol administration. Depressive-like behaviors were evaluated by the tail suspension test and forced swimming test, and anxiety-like behaviors were evaluated by the marble-burying test and elevated plus maze test. The expression of Nrf2 was measured by western blotting. Levels of inflammatory mediators (NF-κB, TNF-α, IL-1β and IL-6) and oxidative stress factors (ROS, MDA, GSH and SOD) were detected by ELISA. The ethanol-induced PC12/BV2 cell injury model was used to elucidate whether the effect of irisin on ethanol-induced neurological injury was related to anti-inflammatory and antioxidant mechanisms. Ethanol-induced ethanol preference and emotional deficits were improved by chronic irisin treatment; however, these improvements were partly reversed by cotreatment with the Nrf2 inhibitor ML385. Further results implied that the improvement effect of irisin on behavioral abnormalities may be related to its anti-inflammatory and antioxidant effects. In detail, irisin inhibited ethanol-induced abnormal expression of ROS and MDA and upregulated the expression of GSH and SOD. Meanwhile, irisin treatment inhibited ethanol-induced overexpression of NF-κB, TNF-α, IL-1β and IL-6 in the hippocampus and cerebral cortex. The regulation of oxidative stress factors by irisin was reversed after ML385 treatment. In the in vitro study, overexpression of oxidative stress factors in ethanol-treated PC12 cells was inhibited by irisin treatment; however, the prevention was reversed after the knockdown of Nrf2 siRNA. Moreover, ethanol-induced overexpression of inflammatory mediators in BV2 cells was also inhibited by irisin treatment. Irisin improved depressive and anxiety-like behaviors induced by ethanol addiction/withdrawal in mice, and this protection was greatly associated with the NF-κB-mediated anti-inflammatory signaling pathway and Nrf2-mediated antioxidative stress signaling pathway.
... Many studies have indicated that the FNDC5/irisin system offers multiple advantages in metabolic diseases, such as an anti-in ammatory response in Alzheimer's disease (AD) by decreasing Aβ (Noda et al. 2018; Kim and Song 2018), antioxidant effects in type 2 diabetes (Zhu et al. 2015), and antiapoptotic effects in lipopolysaccharide-induced liver injury (Li et al. 2021). Moreover, some studies have shown that irisin is bene cial to ethanol-induced liver diseases, such as alcoholic fatty liver disease (AFLD), primary biliary cholangitis (PBC) and alcoholic cirrhosis (AC) (Choi et al. 2014; Waluga et al. 2019). However, most studies still focus on the effect of irisin on peripheral metabolic diseases caused by ethanol. ...
This study aims to investigate the effect of irisin on ethanol-induced behavioral deficits and explore the underlying mechanisms. A mouse model of ethanol addiction/withdrawal was constructed through chronic ethanol administration. Depressive-like behaviors were evaluated by the tail suspension test and forced swimming test, and anxiety-like behaviors were evaluated by the marble-burying test and elevated plus maze test. The expression of Nrf2 was measured by western blotting. Levels of inflammatory mediators (NF-κB, TNF-α, IL-1β and IL-6) and oxidative stress factors (ROS, MDA, GSH and SOD) were detected by ELISA. The ethanol-induced PC12/BV2 cell injury model was used to elucidate whether the effect of irisin on ethanol-induced neurological injury was related to anti-inflammatory and antioxidant mechanisms. Ethanol-induced ethanol preference and emotional deficits were improved by chronic irisin treatment; however, these improvements were partly reversed by cotreatment with the Nrf2 inhibitor ML385. Further results implied that the improvement effect of irisin on behavioral abnormalities may be related to its anti-inflammatory and antioxidant effects. In detail, irisin inhibited ethanol-induced abnormal expression of ROS and MDA and upregulated the expression of GSH and SOD. Meanwhile, irisin treatment inhibited ethanol-induced overexpression of NF-κB, TNF-α, IL-1β and IL-6 in the hippocampus and cerebral cortex. The regulation of oxidative stress factors by irisin was reversed after ML385 treatment. In the in vitro study, overexpression of oxidative stress factors in ethanol-treated PC12 cells was inhibited by irisin treatment; however, the prevention was reversed after the knockdown of Nrf2 siRNA. Moreover, ethanol-induced overexpression of inflammatory mediators in BV2 cells was also inhibited by irisin treatment. Irisin improved depressive and anxiety-like behaviors induced by ethanol addiction/withdrawal in mice, and this protection was greatly associated with the NF-κB-mediated anti-inflammatory signaling pathway and Nrf2-mediated antioxidative stress signaling pathway.
... Most studies indicate a decreased concentration in this group of patients [34][35][36]. However, some studies have shown elevated irisin levels in NAFLD patients [19,37]. There are also data showing no effect on NAFLD on the concentration of this myokine [38]. ...
... In studies assessing the concentration of irisin, imaging tests (US, MR) or liver biopsies are the main methods for diagnosing fatty liver infiltration [19,[34][35][36][37][38][39]. In our study, we made the diagnosis of NAFLD based not only on US but also on HSI and FLI. ...
... In our study, the ELISA Kit (BioVendor-Laboratorní medicína a.s. Czech Republic) was used to determine irisin concentration, as in other studies of NAFLD patients [19,[34][35][36][37][38][39]. It should be emphasized that, in NAFLD patients, no other methods of administering irisin than ELISA were used, which have been used in patients with other than hepatic steatosis diseases [43,44]. ...
Irisin is a cytokine involved in many metabolic pathways occurring, among others, in muscles, adipose tissue and liver. Thus, fluctuations in irisin levels are suggested to be related to metabolic diseases. Therefore, the purpose of our study was to evaluate whether irisin may be associated with non-alcoholic fatty liver disease (NAFLD). A total of 138 patients (70/68 male/female, mean age 65.61 ± 10.44 years) were enrolled in the study. The patients were assigned to the NAFLD group (n = 72, including 46 patients with type 2 diabetes (T2DM]) and the group without NAFLD (n = 66, 31 patients with T2DM). NAFLD was diagnosed based on ultrasound examination, Hepatic Steatosis Index (HSI) and Fatty Liver Index. Baseline anthropometric, blood pressure and biochemical parameters were collected. The serum irisin level was determined using an ELISA test. We observed that NAFLD was associated with an increased concentration of irisin. Moreover, Spearman correlations and linear regression analysis revealed that irisin level correlates with some anthropometric and biochemical parameters such as body mass index, glycated hemoglobin, aspartic aminotransferase, creatinine and urea. Logistic regression analysis depicted that odds for NAFLD increase 1.17 times for each 1 μg/mL rise of irisin concentration. Finally, ROC analysis showed that the concentration of irisin possesses a discriminate capacity for NAFLD and optimal cut points concentration could be designed. The risk of NAFLD in the subgroup with irisin concentration above 3.235 μg/mL was 4.57 times higher than in patients with the lower concentration of irisin. To conclude, the obtained results suggest that irisin concentration is associated with some anthropometric and biochemical parameters and should be further investigated toward its usage as a diagnostic biomarker of NAFLD.
... After excluding 41 duplicates and 84 citations of irisin secretion in patients with NAFLD. However, studies that explored circulating (serum/plasma) irisin levels in NAFLD showed highly contradictive results [13][14][15][16][17][18][19][20][21][22][23], with some noting lower levels in patients with NAFLD, and others showing comparable or even higher levels versus controls. The differences in the ascertainment approaches for NAFLD (liver biopsy versus ultrasonography), the selection of controls [body mass index (BMI)-matched versus unmatched], and the ELISA kits used for irisin measurement represent substantial concerns in interpreting the association between irisin and NAFLD [24]. ...
... based on title/abstract and/or full-text with the reasons listed in Figure 1, 11 studies (6 case-control and 5 cross-sectional) were included [13][14][15][16][17][18][19][20][21][22][23]. ...
... Ten studies with 11 datasets compared circulating irisin in NAFLD (n = 1125) versus any non-NAFLD controls (n = 944) [13,14,[16][17][18][19][20][21][22][23] (Fig. 2A). Meta-analysis showed that circulating irisin was comparable between NAFLD and controls (SMD -0.09, 95% CI: -0.48 to 0.29, I 2 = 92%). ...
Introduction:
Exogenous administration of recombinant irisin may reverse hepatic steatosis and steatohepatitis. However, it remains controversial as to whether nonalcoholic fatty liver disease (NAFLD) shows reduced circulating (serum/plasma) irisin levels. A meta-analysis was conducted to address this issue.
Material and methods:
A literature search of databases was performed up to June 2021. Observational studies that reported circulating irisin in NAFLD ascertained by any methods (e.g. ultrasonography or magnetic resonance) and compared with any controls were eligible for inclusion. Standardized mean differences (SMDs) and 95% confidence intervals (CIs) were obtained using a random-effects meta-analysis model.
Results:
Eleven studies enrolling 1277 NAFLD cases and 944 non-NAFLD controls were included. The approaches used for NAFLD ascertainment included ultrasonography (4 studies), magnetic resonance (3 studies), and liver biopsy (5 studies). Meta-analysis showed that circulating irisin in NAFLD was comparable to any non-NAFLD controls (10 studies with 11 datasets; SMD -0.09, 95% CI: -0.48 to 0.29), including the body mass index (BMI)-matched and lean controls (both p ≥ 0.80). Restricting studies to NAFLD ascertained by magnetic resonance or liver biopsy rather than ultrasonography showed that serum irisin was reduced in NAFLD (5 studies, SMD -0.63, 95% CI: -1.14 to -0.13). Meta-analysis also suggested that circulating irisin did not differ between mild and moderate-to-severe NAFLD (7 studies; SMD 0.02, 95% CI: -0.25 to 0.30), and this association was not significantly moderated by study location (Europe versus Asia).
Conclusions:
Circulating irisin in NAFLD did not differ from any non-NAFLD controls and was unlikely to be affected by disease severity or racial-ethnic difference.
... 61). These observations were verified in patients with metabolic syndrome and concurrent fatty liver, whose systemic irisin concentrations were drastically up-regulated and represented a positive correlation with liver enzymes, homeostatic model assessment of insulin resistance index (HOMA-IR), anthropometry data as well as serum triglycerides(62). ...
Fibronectin type III domain-containing protein 5 (FNDC5) is a transmembrane
protein and the precursor of irisin, which serves as a systemic exerkine/myokine with
multiple origins. Since its discovery in 2012, this hormone-like polypeptide has
rapidly evolved to a component significantly involved in a gamut of metabolic
dysregulations and various liver diseases. After a decade of extensive investigation on
FNDC5/irisin, we are still surrounded by lots of open questions regarding its
diagnostic and therapeutic values. In this review, we first concentrated on the
structure-function relationship of FNDC5/irisin. Next, we comprehensively
summarized the current knowledge and research findings regarding pathogenic
roles/therapeutic applications of FNDC5/irisin in the context of nonalcoholic fatty
liver disease, fibrosis, liver injury due to multiple detrimental insults, hepatic
malignancy and intrahepatic cholestasis of pregnancy. Moreover, the prominent
molecules involved in the underlying mechanisms and signaling pathways were
highlighted. As a result, emerging evidence reveals FNDC5/irisin may act as a proxy
for diagnosing liver disease pathology, a sensitive biomarker for assessing damage
severity, a predisposing factor for surveilling illness progression and a treatment
option with protective/preventive impact, all of which are highly dependent on disease
grading and contextually pathological features.
... Furthermore, increase of irisin levels in circulation was found to be protective against diet-induced weight gain and causes improvement of insulin resistance (IR). 1 The association of irisin levels with physical activity, parameters of glucose and lipid metabolism, obesity and obesity-related morbidities such as type 2 diabetes mellitus (DM), and metabolic syndrome (MetS) have been investigated, and inconsistent results have been reported. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adolescents, with fat accumulation in the liver without any other diseases or alcohol and drug intake that could cause liver disease. The prevalence is increasing in parallel with the increasing prevalence of obesity. ...
... 17 Contradictory results have been reported on the association between irisin and NAFLD in several previous studies. [17][18][19][20]28,29 To the best of our knowledge, there is no study investigating the relationship between circulating irisin levels and NAFLD in children. Therefore, we aimed to determine whether serum irisin levels are related to anthropometric measurements and metabolic and biochemical parameters in obese children with NAFLD. ...
... Contrary to our study, Choi et al. 19 found that circulating irisin levels were higher in those with NAFLD than healthy controls, and those with mild NAFLD than those with severe NAFLD; however, no difference was detected between obese controls and healthy controls. ...
Background:
Irisin is a newly defined myokine which is induced by exercise, which stimulates white fat cells to have the characteristics of brown adipose tissue cell. It thereby causes thermogenesis, energy and weight loss and improvement in insulin sensitivity. These effects of irisin suggest that it may be associated with obesity, insulin resistance and non-alcoholic fatty liver disease (NAFLD).
Methods:
The aim of the present study was to determine the relationship of serum irisin levels in obese children with NAFLD. A total of 60 pubertal obese adolescents (age range: 11-18 yrs) as well as age and sex matched 28 healthy children were included in the study. Thirty of obese patients had NAFLD.
Results:
The median irisin levels were lower in the obese patients both with and without NAFLD when compared with the control group. NAFLD group had a higher BMI than obese controls, however, the irisin levels were not different between these groups. The irisin levels were negatively correlated with BMI, BMI SDS, waist, hip and arm circumferences, waist/hip ratio, triceps-biceps skinfold thickness and AST, ALT levels in the all study groups. However, it was positively correlated with BMI, BMI SDS and waist and hip circumference in the entire obese group and positively with BMI SDS in the NAFLD subgroup.
Conclusions:
Consequently, circulating irisin levels are lower in obese adolescents and negatively correlated with body adiposity. In NAFLD patients, it may be related to steatosis and may decrease with liver damage.
... Despite the positive effects of irisin on metabolic mechanisms, there are conflicting results on irisin correlation with NAFLD events. For instance, the circulating irisin level is significantly higher in non-alcoholic fatty liver disease [110], while intrahepatic triglyceride content is negatively correlated with irisin in obese adult humans [5]. Further studies are needed to verify the assumed inhibiting role of irisin on triglyceride synthesis and decreasing intrahepatic lipid accumulation. ...
Physical exercise is a therapeutic strategy for some systemic and non-systemic complications. Various processes or factors like myokines are involved in an exercise course. Irisin is produced in skeletal muscle during exercise, and its effects resemble many exercise effects. Besides the systemic effects of muscle-derived irisin, this peptide is produced in different tissues. Numerous studies have investigated the underlying molecular mechanisms of irisin effects. Despite some controversies, most studies have demonstrated the improvement of metabolic-related complications and immunomodulatory or regenerative mechanisms in correlation with the circulating level of this peptide or after in vivo/in vitro treatments that have introduced it as a peptide with therapeutic value. This review describes the similarities and differences of the effects in various tissues and their correlation with the most prevalent tissue-related complication to present a view for the mechanism(s) of function, efficacy, and safety of this peptide in each tissue as an exercise effector and endocrine peptide.
... In the liver, irisin has direct anti-steatogenic effects through activation of PPAR-α and upregulation of fibroblast growth factor 21 (FGF21) [49,50]. Several studies [51,52], but not all [53], have shown a negative correlation between irisin and hepatic steatosis severity. ...
Non-alcoholic fatty liver disease (NAFLD), which approximately affects a quarter of the world’s population, has become a major public health concern. Although usually associated with excess body weight, it may also affect normal-weight individuals, a condition termed as lean/non-obese NAFLD. The prevalence of lean/non-obese NAFLD is around 20% within the NAFLD population, and 5% within the general population. Recent data suggest that individuals with lean NAFLD, despite the absence of obesity, exhibit similar cardiovascular- and cancer-related mortality compared to obese NAFLD individuals and increased all-cause mortality risk. Lean and obese NAFLD individuals share several metabolic abnormalities, but present dissimilarities in genetic predisposition, body composition, gut microbiota, and susceptibility to environmental factors. Current treatment of lean NAFLD is aimed at improving overall fitness and decreasing visceral adiposity, with weight loss strategies being the cornerstone of treatment. Moreover, several drugs including PPAR agonists, SGLT2 inhibitors, or GLP-1 receptor agonists could also be useful in the management of lean NAFLD. Although there has been an increase in research regarding lean NAFLD, there are still more questions than answers. There are several potential drugs for NAFLD therapy, but clinical trials are needed to evaluate their efficacy in lean individuals.
... 43,44 Physical activity stimulates irisin that exerts a variety of metabolic effects including thermogenesis. 45 It is possible that irisin reduces the risk of NAFLD. 46 Increased lipolysis in NAFLD results in increased VLDL production and increased circulating levels of VLDL particles, which lead to the generation of small, dense LDL particles that are highly atherogenic. ...
Nonalcoholic fatty liver disease (NAFLD) denotes a condition with excess fat in the liver. The prevalence of NAFLD is increasing, averaging > 25% of the Western population. In 25% of the patients, NAFLD progresses to its more severe form: nonalcoholic steatohepatitis and >25% of these progress to cirrhosis following activation of inflammatory and fibrotic processes. NAFLD is associated with obesity, type 2 diabetes, and the metabolic syndrome and represents a considerable and increasing health burden. In the near future, NAFLD cirrhosis is expected to be the most common cause for liver transplantation. NAFLD patients have an increased risk of developing cardiovascular disease as well as liver-related morbidity. In addition, hepatic steatosis itself appears to represent an independent cardiovascular risk factor. In the present review, we provide an overview of the overlapping mechanisms and prevalence of NAFLD and cardiovascular disease.
