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Asadi M, Haidari F, Bavi Behbahani H, J Chitsazi M, Mohammadi-asl J, Ahmadi-Angali K. Effect of Weight-Loss Diet Combined with Taurine Supplementation on Fasting Levels of Fibroblast Growth Factors19, 21, and 𝛃-klothoCo-Receptor in Obese Women: A Randomized Clinical Trial. JNFS 2025; 10 (1) :103-112
URL: http://jnfs.ssu.ac.ir/article-1-887-en.html
URL: http://jnfs.ssu.ac.ir/article-1-887-en.html
Maryam Asadi * 
, Fatemeh Haidari , Hossein Bavi Behbahani , Maryam J Chitsazi , Javad Mohammadi-asl , Kambiz Ahmadi-Angali
, Fatemeh Haidari , Hossein Bavi Behbahani , Maryam J Chitsazi , Javad Mohammadi-asl , Kambiz Ahmadi-Angali
Department of Nutrition, Shoushtar Faculty of Medical Sciences, Shoushtar, Iran
Keywords: Taurine, Calorie restriction, Weight loss program, Fibroblast growth factors, β-Klotho, Obesity.
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Effect of Weight-Loss Diet Combined with Taurine Supplementation on Fasting Levels of Fibroblast Growth Factors19, 21, and 𝛃-klothoCo-Receptor in Obese Women: A Randomized Clinical Trial
Maryam Asadi; PhD *1, Fatemeh Haidari; PhD 2,3, Hossein Bavi Behbahani; MSc 4, Maryam J Chitsazi; MSc 5, Javad Mohammadi-asl; PhD 6 & Kambiz Ahmadi-Angali; PhD 7
Maryam Asadi; PhD *1, Fatemeh Haidari; PhD 2,3, Hossein Bavi Behbahani; MSc 4, Maryam J Chitsazi; MSc 5, Javad Mohammadi-asl; PhD 6 & Kambiz Ahmadi-Angali; PhD 7
1 Department of Nutrition, Shoushtar Faculty of Medical Sciences, Shoushtar, Iran;2 School of Health, Medical and Applies Sciences, CQ University, Brisbane, Australia; 3 Department of Nutrition, Nutrition and Metabolic Diseases Research Centre, Ahvaz Jundishapur University of Medical sciences, Ahvaz, Iran; 4 Student Research Committee, Ahvaz Junishapur University of Medical Sciences, Ahvaz, Iran; 5 Nutrition and Food Security Research Centre, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; 6 Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; 7 Faculty of Public Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| ARTICLE INFO | ABSTRACT | |
| ORIGINAL ARTICLE | Background: Taurine (Tau) is naturally synthesized in the body from cysteine. It plays a crucial role in lipid and carbohydrate metabolism, increasing energy consumption, reducing inflammation, and controlling appetite. Some research suggests that obesity may be associated with decreased serum Tau levels. This study is the first randomized controlled trial to assess the effectiveness of a Tau supplement in combination with a weight loss intervention on fibroblast growth factors (FGF) 19, 21, and β-Klotho co-receptor in obese women. Methods: Participants were randomly assigned to two groups: a standard weight-loss group receiving 3 g/day of Tau capsules for 8 weeks (n=20) and a standard weight-loss group receiving placebo capsules for 8 weeks (n=18). The weight loss intervention aimed to reduce 30% of the total energy consumed by the participants.A paired t-test and an independent sample t-test were employed to assess parametric continuous data within and between the groups. Analysis of covariance was utilized to control for confounding variables. Results: At post-intervention, there was a significant reduction in mean changes of β-Klotho (P=0.01) in Tau group, compared to the control group. However, there were no significant differences in mean changes of FGF 19 and FGF 21 between the two groups (P>0.05). Conclusion:This study suggests that Tau supplementation alongside a weight loss diet may lead to a reduction in serum levels ofβ-Klothoco-receptor, which could serve as an alternative marker of obesity. | |
| Article History: Received: 8 May 2023 Revised: 22 Jul 2023 Accepted: 28 Jul 2023 |
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| *Corresponding author: Maryamasadi136@gmail.com Nutrition Department, Shoushtar Faculty of Medical Sciences, Shoushtar, Iran. Postal code:6135715794 Tel: +98 613 6224243 |
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| Keywords: Taurine; Calorie restriction; Weight loss program; Fibroblast growth factors; β-Klotho; Obesity. |
Introduction
Obesity, classified as a metabolic disorder, is closely linked to inflammation, hyperlipidemia, and diabetes due to insulin resistance (Murakami, 2015).It ranks as the fifth leading cause of death globally, with a high prevalence rate. In the United States, the prevalence of obesity among individuals aged 20-74 is 34% for females and 31.7% for males. On a global scale, obesity affects 18% of men and 21% of women (Murakami, 2015, Rahmani et al., 2015).Moreover, obesity is a significant contributor to various diseases, including diabetes, ischemic heart disease, and certain types of cancer. Consequently, it reduces lifespan and elevates the cost of treatment for affected individuals (Rahmani et al., 2015).
Fibroblast growth factors (FGFs) play diverse roles in biology, including cellular differentiation, angiogenesis, wound healing, and regulation of metabolism. Two specific FGFs, FGF19 and FGF21, function as endocrine hormones (Degirolamo et al., 2016).These hormones interact with β-klotho co-receptor to activate fibroblast growth factor receptors (FGFRs) (Degirolamo et al., 2016).β-klotho co-receptors are abundantly present in the liver, white adipose tissue (WAT), brown adipose tissue (BAT), and the central nervous system (Lan et al., 2017, Nie et al., 2017). Some evidence suggests the involvement of FGF19 and FGF21 dysfunction in obesity (Babaknejad et al., 2018, Gallego-Escuredo et al., 2015). A clinical trial has revealed that obese individuals have higher serum levels of FGF21 and lower levels of FGF19 compared to individuals with normal metabolism and body mass index (BMI). This indicates a resistance to FGF21 in obese individuals (Gallego-Escuredo et al., 2015). Furthermore, the expression of β-Klotho co-receptor gene significantly reduced in obese patients compared to healthy controls. Obesity-related pro-inflammatory factors may contribute to down regulation of β-Klotho expression. Given that the proper functioning of FGF19 and FGF21 relies on β-Klotho co-receptor, decreased expression of β-Klotho can lead to metabolic disorders (Gallego-Escuredo et al., 2015).Studies have highlighted serum levels of β-Klotho co-receptor as a promising new marker for metabolic diseases (Tayyar et al., 2018, Toloza et al., 2018).Evidence suggests that inflammatory factors derived from adipocytes can diminish the expression of β-Klotho gene (Díaz-Delfín et al., 2012). Therefore, weight loss can be an effective approach in reducing resistance to FGF21 and promoting the up regulation of β-Klotho co-receptor. Conversely, low serum levels of FGF19 have been observed in obese individuals, indicating an overlap in metabolic functions of FGF19 and FGF21 (Gallego-Escuredo et al., 2015).Taking into consideration the potential impact of weight loss on FGFs and β-Klotho co-receptors, (Díaz-Delfín et al., 2012, Gallego-Escuredo et al., 2015, Tayyar et al., 2018, Toloza et al., 2018, Zhang et al., 2015), it is plausible to suggest that weight loss, coupled with the use of nutritional supplements,(Sáez-Lara et al., 2016, Talenezhad et al., 2020)can be an effective approach to combat obesity.
Taurine (2-aminoethylsulfonic acid, Tau) is synthesized through endogenous processes from methionine or cysteine in the human body. Seafood also provides Tau. However, Tau derived from food is carried in small quantities to the body tissues (Haidari et al., 2019). In a clinical study, lower serum levels of Tau were found in obese individuals compared to those who were of normal weight (58 μmol/lvs serum normal range of 65-179 μmol/l) (Rosa et al., 2014). Tau plays an important role in regulating glucose metabolism, lipid metabolism, increasing energy expenditure, reducing inflammation, and controlling appetite. Thus, Tau affects several target tissues, including adipose tissue, liver, muscles, and the nervous system. However, the main effect of Tau in obesity results from its direct effects on adipocytes (Murakami, 2015, Rosa et al., 2014).
A few human studies have investigated the effects of oral Tau supplementation on obesity, but the results have been controversial (Batitucci et al., 2019, De Carvalho et al., 2021, Rosa et al., 2014, Zhang et al., 2004). Furthermore, while Tau is known to play a role in improving energy metabolism and reducing inflammation, its impact on serum levels of FGFs and β-Klotho co-receptor has not yet been investigated. Therefore, for the first time, this randomized clinical study aimed to assess the effect of Tau supplementation in conjunction with a weight-loss intervention on FGF19, FGF21, and β-Klotho co-receptor in obese women.
Materials and Methods
Design and participants
This study was a double-blinded controlled clinical trial conducted at Clinics of Ahvaz Nutrition Therapy. A total of 50 obese women were participated in the study. Inclusion criteria were women aged 18-49 years with a BMI between 30 and 40 kg/m², and their consent to participate. Exclusion criteria included the use of herbal and nutritional supplements, as well as any weight-loss programs involving drugs or surgical procedures in the past six months.
The sample size was determined based on a previous study, considering a 95% confidence interval (CI) and 80% power (α=0.05, β=0.2). Taking into account a 20% attrition rate, 25 obese women were assigned to each group (Rosa et al., 2014).
Participants were randomly allocated to two groups: the standard weight-loss group receiving capsule of Tau (3 g/day) for 8 weeks (n=20), and the standard weight-loss group receiving placebo capsule for 8 weeks (n=18). The allocation of Tau or placebo bottles to each group (A or B) was determined by a third party using random numbers. To maintain blinding, unique codes were used instead of the letters A or B, and the bottles were sealed to ensure similarity in appearance and weight. Both the researcher and participants were unaware of the treatment allocation. The randomization codes were revealed only after the completion of the study protocol by all individuals involved.
Tau capsules (1g, Nutricost Company, Midvale, UT, USA) and placebo capsules (prepared by the Pharmacy Faculty of Ahvaz Jundishapur University of Medical Sciences) were consumed three times daily by Tau + weight loss group and placebo + weight loss group, respectively. To facilitate weight loss, the total energy requirements of participants were reduced by 30%. The macronutrient distribution consisted of 50% carbohydrates, 30% fats, and 20% proteins. A nutritionist specialized in dietetics monitored participants' adherence to the prescribed regimen on a weekly basis.
Measurements
Participants completed a questionnaire that included demographic data, medical records, and information on nutritional supplements. Dietary information was obtained through a 24-hour recall of diet at the beginning and after the intervention. The dietary data was analyzedusing Nut IV software (The Hearst Corporation, San Bruno, CA, USA). Participants were instructed not to make any changes to their dietary habits or physical activities during the study.
The participants' physical activity was assessed using the International Physical Activity Questionnaire (IPAQ) at baseline and the end of the intervention.Body weight and height measurements were taken with a precision of 0.5 kg and 0.1 cm, respectively. BMI was calculated by dividing the weight in kilograms by the square of height in meters. Blood samples (5 ml) were collected after a 10 to 12-hour fasting period before and after the intervention. The separated serum was stored at a temperature of -80°C. Enzyme-linked immunosorbent assay (ELISA) kits from Laboratory Bioassay Technology, China, were used to measure FGF-19 (ng/l), FGF-21 (pg/ml), and β-Klotho co-receptor (nmol/l).
Ethical considerations
This clinical trial was approved by the
Ethics Committee of Ahvaz Jundishapur University of Medical Sciences, Iran, in accordance with the Declaration of Helsinki (Registration Number: IR,AJUMS.REC.1397.590). The trial was also registered in the Iranian Registry of Clinical Trials with the registration number IRCT20131125015542N2.Prior to the intervention, all participants were required to sign a consent form.
Data analysis
The collected data were analysedusing IBM SPSS Statistics version 22 (Armonk, USA). A significance level of P-value<0.05 was considered statistically significant. The normality of the data was assessed using the Kolmogorov-Smirnov test. Categorical variables were analysedusing the chi-square test at baseline. Parametric data within the two groups were analysedusing the paired t-test and independent samples t-test. The Analysis of Covariance test (ANCOVA) was utilized to adjust for confounding variables. Numeric variables were reported as means ± standard deviation (SD), while categorical variables were reported as numbers (percentage).
Results
Figure 1 shows flow diagram of the study. Twelve participants were excluded from the Tau (n=5) and placebo group (n=7) because of their travels and personal circumstances. Table 1 summarizes demographic and anthropometric characteristics of the participants before and after the intervention
There was no difference in baseline characteristics between the two groups. Furthermore, according to Table 2, there was no significant difference in the intake of macro and micro nutrients, as well as physical activity, between the two groups, before and after the intervention.
At baseline, there was no significant difference between the groups on serum FGF19, FGF21, and β-Klotho (P>0.05). The results of the comparisons between the groups and within the study did not show significant differences between the groups in serum FGF21, FGF19 or β-Klotho (P>0.05). However, the mean change of β-Klotho serum level (adjusted for age, dietary intake of energy, macronutrients, micronutrients, BMI, and physical activity) was significantly lower in Tau+weight loss group than placebo+weight loss group after adjustment of the confounding variables (P<0.01) (Table 3).
Discussion
The results of the study demonstrated that supplementation with 3g of Tau combined with a weight loss diet in obese women for eight weeks led to a significant reduction in the serum concentration of β-Klotho co-receptor, which serves as a new indicator of obesity. This reduction remained significant even after adjusting for confounding factors such as age, dietary intake of energy, macronutrients, antioxidant vitamins (such as vitamins A, C, and E), BMI, and physical activity, compared to the control group. However, there were no significant differences observed in serum levels of FGF19 and FGF21 in Tau + weight loss group.
Several uncontrolled studies have explored the relationship between serum concentrations of FGFs and weight loss through diet or surgical methods, yielding conflicting results(Bednarska et al., 2020, Haluzikova et al., 2013, Mai et al., 2011, Mraz et al., 2009, Mráz et al., 2011, Watanabe et al., 2020). In a clinical trial conducted by Mai et al., the effects of a low-calorie diet and physical activity on weight loss were assessed in 30 obese individuals (24 women and 6 men) over a 6-month period. They did not observe any significant change in serum levels of FGF21, and the average weight loss was below 5%(Mai et al., 2011). These findings align with the present study; however, the study designs differed. It appears that a more substantial degree of weight loss may be necessary to achieve a significant change in serum FGF levels.
A cross-sectional study comparing serum levels of FGF21, FGF19, and β-Klotho in 67 overweight women and 18 normal weight women revealed higher levels of these factors in overweight individuals (Bednarska et al., 2020). However, to date, no studies have specifically investigated the effect of diet on serum levels of β-Klotho. In the present study, a significant decrease in serum β-Klotho levels was observed in the intervention group. It is possible that the increased cell resistance to FGF19 and FGF21 in obesity leads to an up regulation of β-Klotho(Babaknejad et al., 2018). Therefore, weight loss combined with Tau supplementation may down regulate β-Klotho in response to reduced inflammation levels.
.
Fibroblast growth factors (FGFs) play diverse roles in biology, including cellular differentiation, angiogenesis, wound healing, and regulation of metabolism. Two specific FGFs, FGF19 and FGF21, function as endocrine hormones (Degirolamo et al., 2016).These hormones interact with β-klotho co-receptor to activate fibroblast growth factor receptors (FGFRs) (Degirolamo et al., 2016).β-klotho co-receptors are abundantly present in the liver, white adipose tissue (WAT), brown adipose tissue (BAT), and the central nervous system (Lan et al., 2017, Nie et al., 2017). Some evidence suggests the involvement of FGF19 and FGF21 dysfunction in obesity (Babaknejad et al., 2018, Gallego-Escuredo et al., 2015). A clinical trial has revealed that obese individuals have higher serum levels of FGF21 and lower levels of FGF19 compared to individuals with normal metabolism and body mass index (BMI). This indicates a resistance to FGF21 in obese individuals (Gallego-Escuredo et al., 2015). Furthermore, the expression of β-Klotho co-receptor gene significantly reduced in obese patients compared to healthy controls. Obesity-related pro-inflammatory factors may contribute to down regulation of β-Klotho expression. Given that the proper functioning of FGF19 and FGF21 relies on β-Klotho co-receptor, decreased expression of β-Klotho can lead to metabolic disorders (Gallego-Escuredo et al., 2015).Studies have highlighted serum levels of β-Klotho co-receptor as a promising new marker for metabolic diseases (Tayyar et al., 2018, Toloza et al., 2018).Evidence suggests that inflammatory factors derived from adipocytes can diminish the expression of β-Klotho gene (Díaz-Delfín et al., 2012). Therefore, weight loss can be an effective approach in reducing resistance to FGF21 and promoting the up regulation of β-Klotho co-receptor. Conversely, low serum levels of FGF19 have been observed in obese individuals, indicating an overlap in metabolic functions of FGF19 and FGF21 (Gallego-Escuredo et al., 2015).Taking into consideration the potential impact of weight loss on FGFs and β-Klotho co-receptors, (Díaz-Delfín et al., 2012, Gallego-Escuredo et al., 2015, Tayyar et al., 2018, Toloza et al., 2018, Zhang et al., 2015), it is plausible to suggest that weight loss, coupled with the use of nutritional supplements,(Sáez-Lara et al., 2016, Talenezhad et al., 2020)can be an effective approach to combat obesity.
Taurine (2-aminoethylsulfonic acid, Tau) is synthesized through endogenous processes from methionine or cysteine in the human body. Seafood also provides Tau. However, Tau derived from food is carried in small quantities to the body tissues (Haidari et al., 2019). In a clinical study, lower serum levels of Tau were found in obese individuals compared to those who were of normal weight (58 μmol/lvs serum normal range of 65-179 μmol/l) (Rosa et al., 2014). Tau plays an important role in regulating glucose metabolism, lipid metabolism, increasing energy expenditure, reducing inflammation, and controlling appetite. Thus, Tau affects several target tissues, including adipose tissue, liver, muscles, and the nervous system. However, the main effect of Tau in obesity results from its direct effects on adipocytes (Murakami, 2015, Rosa et al., 2014).
A few human studies have investigated the effects of oral Tau supplementation on obesity, but the results have been controversial (Batitucci et al., 2019, De Carvalho et al., 2021, Rosa et al., 2014, Zhang et al., 2004). Furthermore, while Tau is known to play a role in improving energy metabolism and reducing inflammation, its impact on serum levels of FGFs and β-Klotho co-receptor has not yet been investigated. Therefore, for the first time, this randomized clinical study aimed to assess the effect of Tau supplementation in conjunction with a weight-loss intervention on FGF19, FGF21, and β-Klotho co-receptor in obese women.
Materials and Methods
Design and participants
This study was a double-blinded controlled clinical trial conducted at Clinics of Ahvaz Nutrition Therapy. A total of 50 obese women were participated in the study. Inclusion criteria were women aged 18-49 years with a BMI between 30 and 40 kg/m², and their consent to participate. Exclusion criteria included the use of herbal and nutritional supplements, as well as any weight-loss programs involving drugs or surgical procedures in the past six months.
The sample size was determined based on a previous study, considering a 95% confidence interval (CI) and 80% power (α=0.05, β=0.2). Taking into account a 20% attrition rate, 25 obese women were assigned to each group (Rosa et al., 2014).
Participants were randomly allocated to two groups: the standard weight-loss group receiving capsule of Tau (3 g/day) for 8 weeks (n=20), and the standard weight-loss group receiving placebo capsule for 8 weeks (n=18). The allocation of Tau or placebo bottles to each group (A or B) was determined by a third party using random numbers. To maintain blinding, unique codes were used instead of the letters A or B, and the bottles were sealed to ensure similarity in appearance and weight. Both the researcher and participants were unaware of the treatment allocation. The randomization codes were revealed only after the completion of the study protocol by all individuals involved.
Tau capsules (1g, Nutricost Company, Midvale, UT, USA) and placebo capsules (prepared by the Pharmacy Faculty of Ahvaz Jundishapur University of Medical Sciences) were consumed three times daily by Tau + weight loss group and placebo + weight loss group, respectively. To facilitate weight loss, the total energy requirements of participants were reduced by 30%. The macronutrient distribution consisted of 50% carbohydrates, 30% fats, and 20% proteins. A nutritionist specialized in dietetics monitored participants' adherence to the prescribed regimen on a weekly basis.
Measurements
Participants completed a questionnaire that included demographic data, medical records, and information on nutritional supplements. Dietary information was obtained through a 24-hour recall of diet at the beginning and after the intervention. The dietary data was analyzedusing Nut IV software (The Hearst Corporation, San Bruno, CA, USA). Participants were instructed not to make any changes to their dietary habits or physical activities during the study.
The participants' physical activity was assessed using the International Physical Activity Questionnaire (IPAQ) at baseline and the end of the intervention.Body weight and height measurements were taken with a precision of 0.5 kg and 0.1 cm, respectively. BMI was calculated by dividing the weight in kilograms by the square of height in meters. Blood samples (5 ml) were collected after a 10 to 12-hour fasting period before and after the intervention. The separated serum was stored at a temperature of -80°C. Enzyme-linked immunosorbent assay (ELISA) kits from Laboratory Bioassay Technology, China, were used to measure FGF-19 (ng/l), FGF-21 (pg/ml), and β-Klotho co-receptor (nmol/l).
Ethical considerations
This clinical trial was approved by the
Ethics Committee of Ahvaz Jundishapur University of Medical Sciences, Iran, in accordance with the Declaration of Helsinki (Registration Number: IR,AJUMS.REC.1397.590). The trial was also registered in the Iranian Registry of Clinical Trials with the registration number IRCT20131125015542N2.Prior to the intervention, all participants were required to sign a consent form.
Data analysis
The collected data were analysedusing IBM SPSS Statistics version 22 (Armonk, USA). A significance level of P-value<0.05 was considered statistically significant. The normality of the data was assessed using the Kolmogorov-Smirnov test. Categorical variables were analysedusing the chi-square test at baseline. Parametric data within the two groups were analysedusing the paired t-test and independent samples t-test. The Analysis of Covariance test (ANCOVA) was utilized to adjust for confounding variables. Numeric variables were reported as means ± standard deviation (SD), while categorical variables were reported as numbers (percentage).
Results
Figure 1 shows flow diagram of the study. Twelve participants were excluded from the Tau (n=5) and placebo group (n=7) because of their travels and personal circumstances. Table 1 summarizes demographic and anthropometric characteristics of the participants before and after the intervention
There was no difference in baseline characteristics between the two groups. Furthermore, according to Table 2, there was no significant difference in the intake of macro and micro nutrients, as well as physical activity, between the two groups, before and after the intervention.
At baseline, there was no significant difference between the groups on serum FGF19, FGF21, and β-Klotho (P>0.05). The results of the comparisons between the groups and within the study did not show significant differences between the groups in serum FGF21, FGF19 or β-Klotho (P>0.05). However, the mean change of β-Klotho serum level (adjusted for age, dietary intake of energy, macronutrients, micronutrients, BMI, and physical activity) was significantly lower in Tau+weight loss group than placebo+weight loss group after adjustment of the confounding variables (P<0.01) (Table 3).
Discussion
The results of the study demonstrated that supplementation with 3g of Tau combined with a weight loss diet in obese women for eight weeks led to a significant reduction in the serum concentration of β-Klotho co-receptor, which serves as a new indicator of obesity. This reduction remained significant even after adjusting for confounding factors such as age, dietary intake of energy, macronutrients, antioxidant vitamins (such as vitamins A, C, and E), BMI, and physical activity, compared to the control group. However, there were no significant differences observed in serum levels of FGF19 and FGF21 in Tau + weight loss group.
Several uncontrolled studies have explored the relationship between serum concentrations of FGFs and weight loss through diet or surgical methods, yielding conflicting results(Bednarska et al., 2020, Haluzikova et al., 2013, Mai et al., 2011, Mraz et al., 2009, Mráz et al., 2011, Watanabe et al., 2020). In a clinical trial conducted by Mai et al., the effects of a low-calorie diet and physical activity on weight loss were assessed in 30 obese individuals (24 women and 6 men) over a 6-month period. They did not observe any significant change in serum levels of FGF21, and the average weight loss was below 5%(Mai et al., 2011). These findings align with the present study; however, the study designs differed. It appears that a more substantial degree of weight loss may be necessary to achieve a significant change in serum FGF levels.
A cross-sectional study comparing serum levels of FGF21, FGF19, and β-Klotho in 67 overweight women and 18 normal weight women revealed higher levels of these factors in overweight individuals (Bednarska et al., 2020). However, to date, no studies have specifically investigated the effect of diet on serum levels of β-Klotho. In the present study, a significant decrease in serum β-Klotho levels was observed in the intervention group. It is possible that the increased cell resistance to FGF19 and FGF21 in obesity leads to an up regulation of β-Klotho(Babaknejad et al., 2018). Therefore, weight loss combined with Tau supplementation may down regulate β-Klotho in response to reduced inflammation levels.
.
In an uncontrolled pilot study conducted by Watanabe et al., serum levels of FGF21 were evaluated in 65 obese patients with non-alcoholic fatty liver disease (NAFLD) who followed a low-calorie diet for 90 days. The study found a decrease in serum FGF21 levels following the weight loss program (Watanabe et al., 2020). This finding contrasts with the results of the present research. Differences in study design, sample size, and duration of follow-up may account for this inconsistency.
In another clinical study conducted by Haluzikovaet al., serum levels of FGF19 and FGF21 were measured in 17 obese women who underwent bariatric sleeve surgery and compared with a healthy control group of normal-weight individuals. Prior to the surgery, obese patients had lower serum levels of FGF19 and higher levels of FGF21 compared to the control group. However, after two years post-surgery, there was a significant increase in serum FGF19 levels and a significant decrease in serum FGF21 levels (Haluzikova et al., 2013). In the current study, no significant differences were found in serum levels of FGF21 and FGF19. These discrepancies may be attributed to differences in the choice of control group, duration of the study, and the BMI of the participants. It is worth noting that the participants in the study by Haluzikovaet al. were morbidly obese. Furthermore, achieving significant changes in FGFs, particularly FGF19, may require an intervention duration longer than 8 weeks, as the alteration of the intestinal tract micro biome plays a critical role in regulating FGF19 gene expression (Gadaleta et al., 2020).
In another clinical trial, the serum levels of FGF21 and FGF19 were investigated in 12 obese patients with type 2 diabetes who underwent a very low-calorie diet for three weeks, compared to a control group of 30 normal-weight individuals. All diabetic patients were treated with fentanyl and exhibited hyperinsulinemia. After the dietary intervention, serum FGF21 levels showed a significant increase, while the increase in serum FGF19 levels was not statistically significant (Mraz et al., 2009, Mráz et al., 2011). These findings differ from the results of the current research. The disparity could be attributed to differences in study design and variations in the metabolic conditions of the participants.
FGF19 and FGF21 are hormones that have the ability to increase energy intake while reducing body weight, insulin levels, blood glucose, and hepatic lipid accumulation (Tomlinson et al., 2002, Xu et al., 2009).These hormones exert their metabolic effects by binding to FGFRs through tyrosine kinase activity. FGF19 and FGF21 form a complex with β-Klotho single-pass transmembrane protein, which leads to decreased gluconeogenesis and increased fatty acid beta-oxidation, insulin sensitivity, adiponectin levels, and thermogenesis. Moreover, they are known to reduce appetite and body weight(Lan et al., 2017, Lin et al., 2017, Owen et al., 2014). However, in obesity, the function of these factors becomes impaired, and the expression of β-Klotho co-receptor gene is reduced due to adipose-derived inflammatory factors. As the function of FGF19 and FGF21 relies on the β-Klotho co-receptor, reduced expression of this protein can contribute to metabolic disorders (Gallego-Escuredo et al., 2015).
Tau has been found to potentially regulate the expression of FGF21 gene in adipocytes and hepatocytes by up regulating energy-related genes such as PPARα, PPARγ, and SIRT1 (Zhang et al., 2015).Additionally, Tau may regulate the expression of FXR gene in intestinal cells through the increase in tauroursodeoxycholic acid (TUDCA) and other Tau-containing bile acid metabolites, as well as through alterations in the intestinal micro biome, thereby affecting the expression of FGF19 gene(Li et al., 2013, Qi et al., 2015, Sayin et al., 2013). Moreover, due to its anti-inflammatory properties, Tau could potentially regulate the expression of FGF19, FGF21, and β-Klotho co-receptor genes by reducing inflammation in the metabolic process (Díaz-Delfín et al., 2012, Gallego-Escuredo et al., 2015).
To the best of our knowledge, this study was the first trial investigating the effect of Tau supplementation along with a weight loss diet on serum levels of FGF19, FGF21, and β-Klotho in obese women. The design of the study was randomized-controlled double-blind clinical trial. To achieve more precise results, main confounding variables were controlled. However, the present study had some limitations. The gene expression of FGFs and β-Klotho was not examined. The study did not accurately adjust for variables such as sleep and wake-up patterns, which could potentially influence the expression of genes affected by FGFs due to the circadian clock (Yu et al., 2020).The participants in this study were advised to maintain regular and timely sleep patterns. Additionally, physical activity, which is known to affect FGF levels, (Xiong et al., 2020)was measured and analysedin the study.Future studies should consider investigating the genetic polymorphisms of the β-Klotho co-receptor, as the function of FGFs is dependent on this co-receptor (Dongiovanni et al., 2020). While all trials, including our study, examined serum FGF levels in a fasting state, it is recommended to measure serum levels after meals to gain a better understanding of the metabolic behaviour of FGF19, which is secreted in response to bile acids.It was not possible in the present research to assess the serum level of Tau, which hinders a precise understanding of the cellular and molecular mechanisms underlying the effects of Tau on FGFs, which are suggested for the future research.
Conclusion
This studyexamined the impact of Tau supplementation (3g/day) for 8 weeks in non-menopausal obese women undergoing a weight loss diet. The results revealed a significant reduction in serum levels of β-Klotho co-receptor compared to Weight loss+placebo group. However, there were no significant differences observed in the levels of FGF19 or FGF21 between the two groups. For the first time, this study investigated the effect of Tau supplementation combined with a weight loss diet on FGF19, FGF21, and β-Klothoco-receptor as a new indicator of obesity.
Acknowledgements
This article was a part of PhD dissertation drafted by Maryam Asadi. We hereby appreciate the participants of the trial.
Authors' contributions
The authors’ contributions are as follows: M Asadi and F Haidari conceived the topic; M Asadi collected data. M Asadi, J Mohammadi-asl, K Ahmadi-Angali and MJ Chitsazi analysed the data; M Asadi, F Haidari, and H BaviBehbahani drafted the manuscript. MJ Chitsazi edited the manuscript. All authors approved the final manuscript.
Conflict of interest
The authors declare that there are no conflicts of interest.
Funding
This RCT was financially supported by Nutrition and Metabolic Disease Research Centre of Ahvaz Jundishapur University of Medical Sciences (Grant number: NRC-9714).
References
Babaknejad N, Nayeri H, Hemmati R, Bahrami S & Esmaillzadeh A 2018. An overview of FGF19 and FGF21: the therapeutic role in the treatment of the metabolic disorders and obesity. Hormone and metabolic research.50(06): 441-452.
Batitucci G, et al. 2019. Taurine supplementation increases irisin levels after high intensity physical training in obese women. Cytokine.123: 154741.
Bednarska S, Fryczak J & Siejka A 2020. Serum β-Klotho concentrations are increased in women with polycystic ovary syndrome. Cytokine.134: 155188.
De Carvalho FG, et al. 2021. Taurine supplementation associated with exercise increases mitochondrial activity and fatty acid oxidation gene expression in the subcutaneous white adipose tissue of obese women. Clinical nutrition.40(4): 2180-2187.
Degirolamo C, Sabba C & Moschetta A 2016. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nature reviews drug discovery.15(1): 51-69.
Díaz-Delfín J, et al. 2012. TNF-α represses β-Klotho expression and impairs FGF21 action in adipose cells: involvement of JNK1 in the FGF21 pathway. Endocrinology.153(9): 4238-4245.
Dongiovanni P, et al. 2020. β-Klotho gene variation is associated with liver damage in children with NAFLD. Journal of hepatology.72(3): 411-419.
Gadaleta RM, et al. 2020. Fibroblast Growth Factor 19 modulates intestinal microbiota and inflammation in presence of Farnesoid X Receptor. EBioMedicine.54: 102719.
Gallego-Escuredo J, et al. 2015. Opposite alterations in FGF21 and FGF19 levels and disturbed expression of the receptor machinery for endocrine FGFs in obese patients. International journal of obesity.39(1): 121-129.
Haidari F, Asadi M & Ahmadi-Angali K 2019. Evaluation of the effect of oral taurine supplementation on fasting levels of fibroblast growth factors, β-Klotho co-receptor, some biochemical indices and body composition in obese women on a weight-loss diet: a study protocol for a double-blind, randomized controlled trial. Trials.20(1): 315.
Haluzikova D, et al. 2013. Laparoscopic sleeve gastrectomy differentially affects serum concentrations of FGF‐19 and FGF‐21 in morbidly obese subjects. Obesity.21(7): 1335-1342.
Lan T, et al. 2017. FGF19, FGF21, and an FGFR1/β-Klotho-activating antibody act on the nervous system to regulate body weight and glycemia. Cell metabolism.26(5): 709-718. e703.
Li F, et al. 2013. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nature communications.4(1): 1-10.
Lin X, Liu YB & Hu H 2017. Metabolic role of fibroblast growth factor 21 in liver, adipose and nervous system tissues. Biomedical reports.6(5): 495-502.
Mai K, et al. 2011. Relation between fibroblast growth factor–21, adiposity, metabolism, and weight reduction. Metabolism.60(2): 306-311.
Mraz M, et al. 2009. Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor‐21 in patients with type 2 diabetes and obesity. Clinical endocrinology.71(3): 369-375.
Mráz M, et al. 2011. Serum concentrations of fibroblast growth factor 19 in patients with obesity and type 2 diabetes mellitus: the influence of acute hyperinsulinemia, very-low calorie diet and PPAR-alpha agonist treatment. Physiological research.60(4): 627-636.
Murakami S 2015. Role of taurine in the pathogenesis of obesity. Molecular nutrition & food research.59(7): 1353-1363.
Nie F, et al. 2017. Serum klotho protein levels and their correlations with the progression of type 2 diabetes mellitus. Journal of diabetes and its complications.31(3): 594-598.
Owen BM, et al. 2014. FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell metabolism.20(4): 670-677.
Qi Y, et al. 2015. Bile acid signaling in lipid metabolism: metabolomic and lipidomic analysis of lipid and bile acid markers linked to anti-obesity and anti-diabetes in mice. Molecular and cell biology of lipids.1851(1): 19-29.
Rahmani A, et al. 2015. Investigation of the Prevalence of Obesity in Iran: a Systematic Review and Meta-Analysis Study. Acta medica Iranica.53(10): 596-607.
Rosa FT, Freitas EC, Deminice R, Jordao AA & Marchini JS 2014. Oxidative stress and inflammation in obesity after taurine supplementation: a double-blind, placebo-controlled study. European journal of nutrition.53(3): 823-830.
Sáez-Lara MJ, Robles-Sanchez C, Ruiz-Ojeda FJ, Plaza-Diaz J & Gil A 2016. Effects of probiotics and synbiotics on obesity, insulin resistance syndrome, type 2 diabetes and non-alcoholic fatty liver disease: a review of human clinical trials. International journal of molecular sciences.17(6): 928.
Sayin SI, et al. 2013. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell metabolism.17(2): 225-235.
Talenezhad N, Mohammadi M, Ramezani-Jolfaie N, Mozaffari-Khosravi H & Salehi-Abargouei A 2020. Effects of l-carnitine supplementation on weight loss and body composition: A systematic review and meta-analysis of 37 randomized controlled clinical trials with dose-response analysis. Clinical nutrition ESPEN.37: 9-23.
Tayyar AT, et al. 2018. Evaluation of FGF-19 and Beta-Klotho as Biomarkers in Patients with Intrahepatic Cholestasis of Pregnancy. Archives of medical science.13(1).
Toloza FJ, et al. 2018. Plasma levels of myonectin but not myostatin or fibroblast-derived growth factor 21 are associated with insulin resistance in adult humans without diabetes mellitus. Frontiers in endocrinology.9: 5.
Tomlinson E, et al. 2002. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology.143(5): 1741-1747.
Watanabe M, et al. 2020. Baseline HOMA IR and Circulating FGF21 Levels Predict NAFLD Improvement in Patients Undergoing a Low Carbohydrate Dietary Intervention for Weight Loss: A Prospective Observational Pilot Study. Nutrients.12(7): 2141.
Xiong Y, Chen Y, Liu Y & Zhang B 2020. Moderate-Intensity Continuous Training Improves FGF21 and KLB Expression in Obese Mice. Biochemistry.85(8): 938-946.
Xu J, et al. 2009. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes.58(1): 250-259.
Yu Z, et al. 2020. Circadian rhythms and bile acid homeostasis: a comprehensive review. Chronobiology international. 1-11.
Zhang F, et al. 2015. Minireview: Roles of Fibroblast Growth Factors 19 and 21 in Metabolic Regulation and Chronic Diseases. Molecular endocrinology 29(10): 1400-1413.
Zhang M, et al. 2004. Beneficial effects of taurine on serum lipids in overweight or obese
non-diabetic subjects. Amino acids.26(3): 267-271.
In another clinical study conducted by Haluzikovaet al., serum levels of FGF19 and FGF21 were measured in 17 obese women who underwent bariatric sleeve surgery and compared with a healthy control group of normal-weight individuals. Prior to the surgery, obese patients had lower serum levels of FGF19 and higher levels of FGF21 compared to the control group. However, after two years post-surgery, there was a significant increase in serum FGF19 levels and a significant decrease in serum FGF21 levels (Haluzikova et al., 2013). In the current study, no significant differences were found in serum levels of FGF21 and FGF19. These discrepancies may be attributed to differences in the choice of control group, duration of the study, and the BMI of the participants. It is worth noting that the participants in the study by Haluzikovaet al. were morbidly obese. Furthermore, achieving significant changes in FGFs, particularly FGF19, may require an intervention duration longer than 8 weeks, as the alteration of the intestinal tract micro biome plays a critical role in regulating FGF19 gene expression (Gadaleta et al., 2020).
In another clinical trial, the serum levels of FGF21 and FGF19 were investigated in 12 obese patients with type 2 diabetes who underwent a very low-calorie diet for three weeks, compared to a control group of 30 normal-weight individuals. All diabetic patients were treated with fentanyl and exhibited hyperinsulinemia. After the dietary intervention, serum FGF21 levels showed a significant increase, while the increase in serum FGF19 levels was not statistically significant (Mraz et al., 2009, Mráz et al., 2011). These findings differ from the results of the current research. The disparity could be attributed to differences in study design and variations in the metabolic conditions of the participants.
FGF19 and FGF21 are hormones that have the ability to increase energy intake while reducing body weight, insulin levels, blood glucose, and hepatic lipid accumulation (Tomlinson et al., 2002, Xu et al., 2009).These hormones exert their metabolic effects by binding to FGFRs through tyrosine kinase activity. FGF19 and FGF21 form a complex with β-Klotho single-pass transmembrane protein, which leads to decreased gluconeogenesis and increased fatty acid beta-oxidation, insulin sensitivity, adiponectin levels, and thermogenesis. Moreover, they are known to reduce appetite and body weight(Lan et al., 2017, Lin et al., 2017, Owen et al., 2014). However, in obesity, the function of these factors becomes impaired, and the expression of β-Klotho co-receptor gene is reduced due to adipose-derived inflammatory factors. As the function of FGF19 and FGF21 relies on the β-Klotho co-receptor, reduced expression of this protein can contribute to metabolic disorders (Gallego-Escuredo et al., 2015).
Tau has been found to potentially regulate the expression of FGF21 gene in adipocytes and hepatocytes by up regulating energy-related genes such as PPARα, PPARγ, and SIRT1 (Zhang et al., 2015).Additionally, Tau may regulate the expression of FXR gene in intestinal cells through the increase in tauroursodeoxycholic acid (TUDCA) and other Tau-containing bile acid metabolites, as well as through alterations in the intestinal micro biome, thereby affecting the expression of FGF19 gene(Li et al., 2013, Qi et al., 2015, Sayin et al., 2013). Moreover, due to its anti-inflammatory properties, Tau could potentially regulate the expression of FGF19, FGF21, and β-Klotho co-receptor genes by reducing inflammation in the metabolic process (Díaz-Delfín et al., 2012, Gallego-Escuredo et al., 2015).
To the best of our knowledge, this study was the first trial investigating the effect of Tau supplementation along with a weight loss diet on serum levels of FGF19, FGF21, and β-Klotho in obese women. The design of the study was randomized-controlled double-blind clinical trial. To achieve more precise results, main confounding variables were controlled. However, the present study had some limitations. The gene expression of FGFs and β-Klotho was not examined. The study did not accurately adjust for variables such as sleep and wake-up patterns, which could potentially influence the expression of genes affected by FGFs due to the circadian clock (Yu et al., 2020).The participants in this study were advised to maintain regular and timely sleep patterns. Additionally, physical activity, which is known to affect FGF levels, (Xiong et al., 2020)was measured and analysedin the study.Future studies should consider investigating the genetic polymorphisms of the β-Klotho co-receptor, as the function of FGFs is dependent on this co-receptor (Dongiovanni et al., 2020). While all trials, including our study, examined serum FGF levels in a fasting state, it is recommended to measure serum levels after meals to gain a better understanding of the metabolic behaviour of FGF19, which is secreted in response to bile acids.It was not possible in the present research to assess the serum level of Tau, which hinders a precise understanding of the cellular and molecular mechanisms underlying the effects of Tau on FGFs, which are suggested for the future research.
Conclusion
This studyexamined the impact of Tau supplementation (3g/day) for 8 weeks in non-menopausal obese women undergoing a weight loss diet. The results revealed a significant reduction in serum levels of β-Klotho co-receptor compared to Weight loss+placebo group. However, there were no significant differences observed in the levels of FGF19 or FGF21 between the two groups. For the first time, this study investigated the effect of Tau supplementation combined with a weight loss diet on FGF19, FGF21, and β-Klothoco-receptor as a new indicator of obesity.
Acknowledgements
This article was a part of PhD dissertation drafted by Maryam Asadi. We hereby appreciate the participants of the trial.
Authors' contributions
The authors’ contributions are as follows: M Asadi and F Haidari conceived the topic; M Asadi collected data. M Asadi, J Mohammadi-asl, K Ahmadi-Angali and MJ Chitsazi analysed the data; M Asadi, F Haidari, and H BaviBehbahani drafted the manuscript. MJ Chitsazi edited the manuscript. All authors approved the final manuscript.
Conflict of interest
The authors declare that there are no conflicts of interest.
Funding
This RCT was financially supported by Nutrition and Metabolic Disease Research Centre of Ahvaz Jundishapur University of Medical Sciences (Grant number: NRC-9714).
References
Babaknejad N, Nayeri H, Hemmati R, Bahrami S & Esmaillzadeh A 2018. An overview of FGF19 and FGF21: the therapeutic role in the treatment of the metabolic disorders and obesity. Hormone and metabolic research.50(06): 441-452.
Batitucci G, et al. 2019. Taurine supplementation increases irisin levels after high intensity physical training in obese women. Cytokine.123: 154741.
Bednarska S, Fryczak J & Siejka A 2020. Serum β-Klotho concentrations are increased in women with polycystic ovary syndrome. Cytokine.134: 155188.
De Carvalho FG, et al. 2021. Taurine supplementation associated with exercise increases mitochondrial activity and fatty acid oxidation gene expression in the subcutaneous white adipose tissue of obese women. Clinical nutrition.40(4): 2180-2187.
Degirolamo C, Sabba C & Moschetta A 2016. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nature reviews drug discovery.15(1): 51-69.
Díaz-Delfín J, et al. 2012. TNF-α represses β-Klotho expression and impairs FGF21 action in adipose cells: involvement of JNK1 in the FGF21 pathway. Endocrinology.153(9): 4238-4245.
Dongiovanni P, et al. 2020. β-Klotho gene variation is associated with liver damage in children with NAFLD. Journal of hepatology.72(3): 411-419.
Gadaleta RM, et al. 2020. Fibroblast Growth Factor 19 modulates intestinal microbiota and inflammation in presence of Farnesoid X Receptor. EBioMedicine.54: 102719.
Gallego-Escuredo J, et al. 2015. Opposite alterations in FGF21 and FGF19 levels and disturbed expression of the receptor machinery for endocrine FGFs in obese patients. International journal of obesity.39(1): 121-129.
Haidari F, Asadi M & Ahmadi-Angali K 2019. Evaluation of the effect of oral taurine supplementation on fasting levels of fibroblast growth factors, β-Klotho co-receptor, some biochemical indices and body composition in obese women on a weight-loss diet: a study protocol for a double-blind, randomized controlled trial. Trials.20(1): 315.
Haluzikova D, et al. 2013. Laparoscopic sleeve gastrectomy differentially affects serum concentrations of FGF‐19 and FGF‐21 in morbidly obese subjects. Obesity.21(7): 1335-1342.
Lan T, et al. 2017. FGF19, FGF21, and an FGFR1/β-Klotho-activating antibody act on the nervous system to regulate body weight and glycemia. Cell metabolism.26(5): 709-718. e703.
Li F, et al. 2013. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nature communications.4(1): 1-10.
Lin X, Liu YB & Hu H 2017. Metabolic role of fibroblast growth factor 21 in liver, adipose and nervous system tissues. Biomedical reports.6(5): 495-502.
Mai K, et al. 2011. Relation between fibroblast growth factor–21, adiposity, metabolism, and weight reduction. Metabolism.60(2): 306-311.
Mraz M, et al. 2009. Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor‐21 in patients with type 2 diabetes and obesity. Clinical endocrinology.71(3): 369-375.
Mráz M, et al. 2011. Serum concentrations of fibroblast growth factor 19 in patients with obesity and type 2 diabetes mellitus: the influence of acute hyperinsulinemia, very-low calorie diet and PPAR-alpha agonist treatment. Physiological research.60(4): 627-636.
Murakami S 2015. Role of taurine in the pathogenesis of obesity. Molecular nutrition & food research.59(7): 1353-1363.
Nie F, et al. 2017. Serum klotho protein levels and their correlations with the progression of type 2 diabetes mellitus. Journal of diabetes and its complications.31(3): 594-598.
Owen BM, et al. 2014. FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell metabolism.20(4): 670-677.
Qi Y, et al. 2015. Bile acid signaling in lipid metabolism: metabolomic and lipidomic analysis of lipid and bile acid markers linked to anti-obesity and anti-diabetes in mice. Molecular and cell biology of lipids.1851(1): 19-29.
Rahmani A, et al. 2015. Investigation of the Prevalence of Obesity in Iran: a Systematic Review and Meta-Analysis Study. Acta medica Iranica.53(10): 596-607.
Rosa FT, Freitas EC, Deminice R, Jordao AA & Marchini JS 2014. Oxidative stress and inflammation in obesity after taurine supplementation: a double-blind, placebo-controlled study. European journal of nutrition.53(3): 823-830.
Sáez-Lara MJ, Robles-Sanchez C, Ruiz-Ojeda FJ, Plaza-Diaz J & Gil A 2016. Effects of probiotics and synbiotics on obesity, insulin resistance syndrome, type 2 diabetes and non-alcoholic fatty liver disease: a review of human clinical trials. International journal of molecular sciences.17(6): 928.
Sayin SI, et al. 2013. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell metabolism.17(2): 225-235.
Talenezhad N, Mohammadi M, Ramezani-Jolfaie N, Mozaffari-Khosravi H & Salehi-Abargouei A 2020. Effects of l-carnitine supplementation on weight loss and body composition: A systematic review and meta-analysis of 37 randomized controlled clinical trials with dose-response analysis. Clinical nutrition ESPEN.37: 9-23.
Tayyar AT, et al. 2018. Evaluation of FGF-19 and Beta-Klotho as Biomarkers in Patients with Intrahepatic Cholestasis of Pregnancy. Archives of medical science.13(1).
Toloza FJ, et al. 2018. Plasma levels of myonectin but not myostatin or fibroblast-derived growth factor 21 are associated with insulin resistance in adult humans without diabetes mellitus. Frontiers in endocrinology.9: 5.
Tomlinson E, et al. 2002. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology.143(5): 1741-1747.
Watanabe M, et al. 2020. Baseline HOMA IR and Circulating FGF21 Levels Predict NAFLD Improvement in Patients Undergoing a Low Carbohydrate Dietary Intervention for Weight Loss: A Prospective Observational Pilot Study. Nutrients.12(7): 2141.
Xiong Y, Chen Y, Liu Y & Zhang B 2020. Moderate-Intensity Continuous Training Improves FGF21 and KLB Expression in Obese Mice. Biochemistry.85(8): 938-946.
Xu J, et al. 2009. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes.58(1): 250-259.
Yu Z, et al. 2020. Circadian rhythms and bile acid homeostasis: a comprehensive review. Chronobiology international. 1-11.
Zhang F, et al. 2015. Minireview: Roles of Fibroblast Growth Factors 19 and 21 in Metabolic Regulation and Chronic Diseases. Molecular endocrinology 29(10): 1400-1413.
Zhang M, et al. 2004. Beneficial effects of taurine on serum lipids in overweight or obese
non-diabetic subjects. Amino acids.26(3): 267-271.
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Received: 2023/05/8 | Published: 2025/02/4 | ePublished: 2025/02/4
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