Hypocaloric Diet Prevents the Decrease in FGF21 Elicited by High Phosphorus Intake

Objective: This study aimed to investigate the effects of Perga supplementation on glucose metabolism, body weight regulation, and amyloid-beta (Aβ) accumulation in a streptozotocin (STZ)-induced type 2 diabetes (T2D) rat model, focusing specifically on insulin, leptin, and fibroblast growth factor 21 (FGF21) signaling pathways. Methods: Male Wistar rats were divided into Sham (S), T2D, and T2D+Perga (T2DP) groups. T2D was induced by a single intraperitoneal (i.p.) STZ injection (60 mg/kg). Perga (200 mg/kg/day) was administered to the T2DP group by gavage 14 days after diabetes induction. Plasma and brain insulin and leptin levels, liver and plasma FGF21 concentrations, Homeostasis Model Assessment of Beta Cell Function (HOMA-β) index, fasting glucose levels, body weight changes, and brain amyloid-beta (Aβ) accumulation were evaluated. Results: STZ-induced T2D resulted in hypoinsulinemia, decreased HOMA-β scores, weight loss, reduced plasma leptin, increased brain leptin, decreased FGF21 levels, and significant Aβ accumulation in the hippocampus. Perga treatment significantly improved plasma and brain insulin levels, increased HOMA-β, reduced fasting glucose, and attenuated weight loss. Plasma leptin levels returned to normal, brain leptin levels decreased, and hippocampus Aβ burden was significantly reduced. In addition, perga supplementation almost normalized liver and plasma FGF21 levels. Conclusion: Perga supplementation effectively ameliorates metabolic dysfunction and neurodegenerative markers in the T2D model. Its regulatory effects on insulin, leptin, and FGF21 signaling highlight its potential as a natural therapeutic agent in managing T2D and associated AD-like pathology. Further research is needed to evaluate its clinical applicability.

Fibroblast growth factor 21 (FGF21) and ketone bodies are markers of metabolic dysregulation, independently associated with metabolic-dysfunction-associated steatotic liver disease (MASLD) and mortality. We studied their interaction with MASLD and all-cause mortality in 6025 participants from the Prevention of Renal and Vascular End-stage Disease (PREVEND) cohort. Plasma FGF21 (immunoassay) and ketone body concentrations (nuclear magnetic resonance spectroscopy) were measured at baseline. A Fatty Liver Index ≥60 was used as a proxy of MASLD. Logistic regression assessed associations with MASLD, and Cox models evaluated all-cause mortality over a median follow-up of 10.3 years. FGF21 and ketone bodies were not correlated (r = 0.02, p = 0.06), but FGF21 (OR: 1.93 [1.81-2.05], p < 0.001) and ketone bodies (OR: 1.29 [1.19-2.05], p < 0.001) were independent of each other associated with MASLD, with a positive interaction (p = 0.004). Higher FGF21 (HR: 1.24, 95% CI: 1.16-1.32, p < 0.001) and ketone bodies (HR: 1.46, 95% CI: 1.34-1.59, p < 0.001) were associated with mortality, as well as with a positive interaction (p = 0.038). After adjustment for potential confounders, only ketone bodies remained independently associated, while the association of FGF21 became dependent on ketone body levels (interaction p = 0.005). These biomarkers may serve as integrated metabolic stress markers, improving risk stratification for MASLD and adverse outcomes.

Fibroblast growth factor 21 (FGF21) regulates energy expenditure (EE) and influences weight change during low-protein overfeeding in rodent models. The change in EE after a low-protein overfeeding diet is a predictor of weight change in humans and a feature of the "thrifty" metabolic phenotype. However, there are no studies showing an association between circulating FGF21 and diet-related EE in humans. We assessed the changes in plasma FGF21 concentrations after 24 h of seven dietary interventions with different macronutrient content while in a whole-room indirect calorimeter in 64 healthy subjects with normal glucose regulation. Plasma FGF21 concentration consistently increased by threefold only after the two low-protein (3%) overfeeding diets, one high in carbohydrate (75%) and the other high in fat (46%), with larger increases in FGF21 being associated with greater increases in 24-h EE. Subjects with smaller increases in FGF21 after the low-protein high-fat diet gained more weight after 6 months in free-living conditions. Therefore, the individual predisposition to weight gain over time can be assessed by 24-h overfeeding a low-protein diet and measurements of plasma FGF21 concentrations. Individuals with a blunted FGF21 response to a low-protein diet have a thrifty metabolism and are at risk for future weight gain.

PurposeMalnutrition during childhood precedes growth failure and affects the child’s well-being later in life. This study aims to investigate the potency of iron-fortified klutuk banana (Musa balbisiana Colla) flour on growth parameters and fibroblast growth factor 21 (FGF21) expression in malnourished rat model.Design/methodology/approachRats were allocated into normal control (NC), untreated malnutrition (MC), malnutrition + iron-fortified klutuk banana flour (IBF) and malnutrition + Indonesian Government-issued biscuit (GB). Malnutrition was induced by an isoenergetic low-protein diet for five weeks. The IBF and GB groups were supplemented with IBF 1.2 g/200 gBW and GB 1.2 g/200 gBW, respectively, via gavage daily for three weeks. The body weight and length, the levels of plasma and liver FGF21 and red blood cell indices were analyzed.FindingsAfter three weeks of supplementation, the IBF group showed higher body weight (245 ± 13.6 g vs 201.8 ± 16.3 g; p = 0.0004) and length (20.9 ± 0.5 cm vs 19.8 ± 0.5 cm; p = 0.021) compared with the untreated group. The plasma FGF21 level decreased in the IBF group (p = 0.034). The IBF group altered mean corpuscular volume and mean corpuscular hemoglobin, suggesting the IBF might attenuate malnutrition-induced anemia. Overall, the IBF prevented growth failure in malnourished condition. This might be mediated by the suppression of FGF21 expression, along with the prevention of malnutrition and anemia.Originality/valueThis study provides preliminary information about the potential use of rarely consumed banana, klutuk banana, as a supplement to treat malnutrition. This study might help the developing countries to eliminate the widespread malnutrition in economically challenged communities.

Fibroblast growth factor 21 (FGF-21) is an atypical member of the FGF family. It act as an endocrine hormone which affects energy balance. In humans FGF-21 was correlated with obesity. The relationship of FGF-21 and starvation in the course of inflammatory bowel diseases (IBD) is unknown. Therefore the FGF-21 concentrations in children with IBD (n=22) and obese children (n=17) were investigated. Subjects were in similar age (14±3 ys.). The mean BMI of obese children were 30±6 kg/m2 whereas in IBD group 16±2,2 kg/m2. The FGF-21 in IBD children were measured triple - in acute stage of the disease, during the treatment and in the remission. FGF-21 concentrations were determined in fasting serum samples using RIA. The highest FGF-21 concentrations (mean 0,7±0,16 ng/ml) were noted in acute stage of IBD. The results in samples taken during the treatment and in remission were similar (0,53±0,17 ng/ml, 0,48±0,09 ng/ml, respectively; p< 0,05 as compare to results determined in acute stage of disease). The mean concentration of FGF- 21 in obese subject was 0,58±0,12 ng/ml; and this value also was significantly lower than observed in acute stage of IBD. The serum levels of FGF-21 in obese group and IBD children during remission correlate with BMI (r=50; p< 0,05). These results suggest that FGF-21 concentration reflect the imbalance in energy intake/expenditure, however the inflammation in IBD increase serum levels of this parameter. Therefore usefulness of FGF-21 as a marker of energy balance in acute stage of IBD and probably in other inflammatory disorders is limited.

Fibroblast growth factor 21 (FGF-21), a potent activator of glucose uptake, has been proposed to be related to insulin resistance, metabolic syndrome (MetS), nonalcoholic fatty liver disease (NAFLD), and weight status. Our objective was to study the relationships between FGF-21, parameters of MetS, and NAFLD before and after weight loss in obese children. This was a cross-sectional comparison between obese and normal-weight children and longitudinal 1-yr follow-up study in obese children participating in a lifestyle intervention in a primary care setting. Patients included 60 obese and 40 lean children of same age, gender, and pubertal stage. The outpatient 1-yr intervention program was based on exercise, behavior, and nutrition therapy. We evaluated fasting serum FGF-21, weight status [body mass index (BMI) expressed as sd score (SDS)], body fat, insulin resistance index (homeostasis model assessment), leptin, transaminases, free fatty acids (FFA), waist circumference, blood pressure, and lipids. Compared with the normal-weight children, obese children demonstrated significantly (P < 0.001) increased FGF-21, leptin, and homeostasis model assessment levels. FGF-21 was significantly (P < 0.05) correlated to BMI, SDS-BMI, FFA, and leptin both in cross-sectional and longitudinal analyses but not to any additional analyzed parameter. Children with and without MetS or NAFLD did not differ significantly with respect to their FGF-21 concentrations. A decrease of SDS-BMI was associated with a significant (P = 0.038) decrease of FGF-21 levels (mean -34%). FGF-21 concentrations are reversibly increased in obese children and are related to leptin and FFA. However, our data do not support a significant relationship between FGF-21, insulin resistance, and features of MetS or NAFLD in children.

Myokine secretion following moderate-intensity endurance exercise under different environmental temperatures

Fibroblast growth factor 21 (FGF21) is increased acutely by carbohydrate ingestion and is elevated in patients with type 2 diabetes (T2D). However, the physiological significance of increased FGF21 in humans remains largely unknown. We examined whether FGF21 contributed to the metabolic improvements observed following treatment of patients with T2D with either triple (metformin/pioglitazone/exenatide) or conventional (metformin/insulin/glipizide) therapy for 3 yr. Forty-six patients with T2D were randomized to receive either triple or conventional therapy to maintain HbA1c < 6.5%. A 2-h 75-g oral glucose tolerance test (OGTT) was performed at baseline and following 3 years of treatment to assess glucose tolerance, insulin sensitivity, and β-cell function. Plasma total and bioactive FGF21 levels were quantitated before and during the OGTT at both visits. Patients in both treatment arms experienced significant improvements in glucose control, but insulin sensitivity and β-cell function were markedly increased after triple therapy. At baseline, FGF21 levels were regulated acutely during the OGTT in both groups. After treatment, fasting total and bioactive FGF21 levels were significantly reduced in patients receiving triple therapy, but there was a relative increase in the proportion of bioactive FGF21 compared with that observed in conventionally treated subjects. Relative to baseline studies, triple therapy treatment also significantly modified FGF21 levels in response to a glucose load. These changes in circulating FGF21 were correlated with markers of improved glucose control and insulin sensitivity. Alterations in the plasma FGF21 profile may contribute to the beneficial metabolic effects of pioglitazone and exenatide in human patients with T2D.NEW & NOTEWORTHY In patients with T2D treated with a combination of metformin/pioglitazone/exenatide (triple therapy), we observed reduced total and bioactive plasma FGF21 levels and a relative increase in the proportion of circulating bioactive FGF21 compared with that in patients treated with metformin and sequential addition of glipizide and basal insulin glargine (conventional therapy). These data suggest that FGF21 may contribute, at least in part, to the glycemic benefits observed following combination therapy in patients with T2D.

Mitiglinide treatment may decreases plasma fibroblast growth factor-21 levels in individuals with new-onset T2DM

Aging increases the prevalence of glucose intolerance, but exercise improves glucose homeostasis. The fibroblast growth factor 21 (FGF21)-adiponectin axis helps regulate glucose metabolism. However, the role of FGF21 in mediating glucose metabolism with aging and exercise remains unknown. This study examined whether FGF21 responses to a glucose challenge are associated with habitual exercise, aging and glucose regulation. Eighty age- and sex-matched healthy individuals were assigned to young sedentary and active (≤36 yr, n = 20 each group) and older sedentary and active (≥45 yr, n = 20 each group) groups. Fasted and postprandial blood glucose concentration and plasma concentration of insulin, FGF21, and adiponectin were determined during an oral glucose tolerance test (OGTT). During the OGTT, glucose concentrations were 9% higher (P = 0.008) and FGF21 concentrations were 58% higher (P = 0.014) in the older than the younger group, independent of activity status. Active participants had 40% lower insulin concentration and 53% lower FGF21 concentration than sedentary participants, independent of age (all P < 0.001). Adiponectin concentration during the OGTT did not differ by age (P = 0.448) or activity status (P = 0.611). Within the younger group, postprandial glucose, insulin and FGF21 concentrations during the OGTT were lower in active than in sedentary participants. In the older group, only postprandial insulin and FGF21 concentrations were lower in active participants. FGF21, but not adiponectin, response during the OGTT is higher in older than younger adults and lower in active than sedentary individuals. Exercise-associated reduction in OGTT glucose concentrations was observed in younger but not older adults.

Inflammation contributes to the development of type 2 diabetes mellitus (T2DM). While South Asians are more prone to develop T2DM than Europids, the inflammatory phenotype of the South Asian population remains relatively unknown. Therefore, we aimed to investigate potential differences in circulating levels of inflammation-related proteins in South Asians compared with Europids with T2DM. In this secondary analysis of three randomized controlled trials, relative plasma levels of 73 inflammation-related proteins were measured using an Olink Target Inflammation panel and the serum fibroblast growth factor 21 (FGF21) concentration using an ELISA kit in Dutch South Asians (n = 47) and Dutch Europids (n = 49) with T2DM. Of the 73 inflammation-related proteins, the relative plasma levels of six proteins were higher (stem cell factor, caspase-8, C-C motif chemokine ligand 28, interferon-gamma, sulfotransferase 1A1 and cystatin D; q-value <0.05), while relative levels of six proteins were lower (FGF21, human fibroblast collagenase, interferon-8, C-C motif chemokine ligand 4, C-X-C motif chemokine ligand 6 and monocyte chemoattractant protein-1; q-value <0.05) in South Asians compared with Europids. Of these, the effect size of FGF21 was the largest, particularly in females. We validated this finding by assessing the FGF21 concentration in serum. The FGF21 concentration was indeed lower in South Asians compared with Europids with T2DM in both males (-42.2%; P < 0.05) and females (-58.5%; P < 0.001). Relative plasma levels of 12 inflammation-related proteins differed between South Asians and Europids with T2DM, with a significantly pronounced reduction in FGF21. In addition, the serum FGF21 concentration was significantly lower in South Asian males and females compared with Europids. Whether low FGF21 is an underlying cause or consequence of T2DM in South Asians remains to be determined. ClinicalTrials.gov (NCT01761318, registration date 20-12-2012; NCT02660047, registration date 21-03-2018; and NCT03012113, registration date 06-01-2017).

Insufficient expression of hepatic fibroblast growth factor 21 (FGF21) and stromal cell-derived factor 2 like 1 (Sdf2l1) reportedly leads to insulin resistance and hepatosteatosis in obesity and type 2 diabetes. On the other hand, increased expression of hepatic serotonin receptor 2a (htr2a) in diet-induced obesity contributes to hepatosteatosis. Here we show that increases in circulating FGF21 levels and expression of hepatic FGF21 preceded weight gain, hyperinsulinemia, and hyperglycemia in C57BLJ6 mice fed a high-fat diet. Expression of hepatic htr2a and Sdf2l1 increased in insulin-resistant mice fed a high-fat diet. Intake of whey protein isolate decreased plasma FGF21 levels and expression of hepatic FGF21 in mice fed either a high-fat diet or a chow diet, whereas it only suppressed the overexpression of hepatic Sdf2 and htr2a in insulin-resistant mice fed a high-fat diet. Moreover, intake of whey protein isolate decreased plasma serotonin levels in mice fed either a high-fat diet or a chow diet. Genetic inhibition of tryptophan hydroxylase 1 decreased hepatic FGF21 expression and plasma FGF21 levels in mice. These findings suggest that increased hepatic FGF21 production precedes diet-induced weight gain, hyperinsulinemia, and hyperglycemia, and that intake of whey protein isolate could inhibit hepatic FGF21 production by suppressing peripheral serotonin synthesis.

Lifestyle, environment and excess body weight are not only associated with an increased risk of metabolic disorders, such as type 2 diabetes, but also to other pathological processes, such as infertility. A hormone produced mainly by the liver called fibroblast growth factor 21 (FGF21) is closely linked to the energy status and is increased in patients suffering from obesity or insulin resistance. Recently, FGF21 has been shown to be associated with female fertility disorders, but no or few data about the role of FGF21 on human male fertility has been described. In the present study, FGF21 was measured in the seminal fluid at a lower level in comparison to the blood level. Thus, in the present in vitro study, we aimed to decipher the FGF21 system in human semen. To evaluate the putative role of FGF21 on spermatozoa function, we incubated human spermatozoa with increasing concentrations of recombinant human FGF21. The FGF21 in seminal fluid is potentially produced by male reproductive tract tissues. In spermatozoa, the FGF21 signal was transduced by the two main receptors FGFR1-c and FGFR3 and the cofactor β-klotho, which are colocalized in the middle piece of spermatozoa and stimulated the PI3K/Akt and MAPK pathways. Finally, in vitro treatment by FGF21 significantly increased sperm motility and ATP levels. Concomitantly, exposure to FGF21 improved the oxidative stress, as a lower ROS level was observed. Overall, these results seem to indicate that the metabolic factor, FGF21, positively modifies the activity and quality of the parameters of human spermatozoa.

Myokines are proteins produced by muscle cells that regulate muscle growth and metabolism. In livestock species, little is known about most myokines or their physiological impact. While FGF-21 has been examined in humans and model species for its roles in muscle development, regeneration, and metabolism, it is important to characterize its expression in livestock, such as beef cattle. This study assessed the quantity and temporal abundance of fibroblast growth factor 21 (FGF-21) expression, from cultured bovine satellite cells (BSC). BSC were isolated from the semimembranosus muscle of 3-month-old (n = 3) and 11-month-old (n = 3) commercially raised angus-based beef steers. BSC were cultured on Matrigel in Dulbecco’s Modified Eagle Medium with 10% Fetal Bovine Serum until 70% confluency. At this time, the media was replaced with fresh media representing time zero. Cells and media were collected at times 0-, 12-, 24-, 48-, 72-, and 96-hour with zero serving as the baseline. All experiments included three biological and three technical replicates. The content of myokines including FGF-21, were analyzed in the sample’s media using a commercial ELISA kit and cells were collected and stored for gene expression analysis. Statistical analysis was completed using the GLIMMIX procedure in SAS. A repeated measures analysis was used to evaluate the fixed effects of age, time, and age×time interaction. Contrasts were used to identify whether the baseline was statistically different from the other timepoints, and Tukey-Kramer adjustments were made. Significance was determined at P ≤ 0.05. There was an interaction effect between age and time (P &amp;lt; 0.0001). The media from the BSC of the 11-month-old steers had greater (P &amp;lt; 0.0001) FGF-21 concentrations than that of the 3-month-old steers at every time point. When evaluating each time in comparison with the baseline of each age independently, there were differences between 0 and 12 hour (P &amp;lt; 0.0001) and 0 and 24 hour (P = 0.002) for the 3-month-old steer BSC, as well as 0 and 12 hour (P = 0.0003) for 11-month-old steer BSC. This study confirms that the myokine FGF-21 is produced by cultured BSC, and in differing quantities depending on the age of the steer at harvest. The observed differences in FGF-21 production in cultured cells harvested from 3- to 11-month-old steers may in part be responsible for some of the differences in growth patterns in muscle cells at these ages. The authors postulate that these data represent the first report of FGF-21 expression in cultured bovine satellite cells.

Introduction. Fibroblast growth factor-21 (FGF21) regulates glucose, lipid, and energy homeostasis. Retinol-binding protein-4 (RBP4) controls metabolic and proliferative cell functions. Aims and methods. Aims of the study were to assess (1) serum FGF21 and RBP4 levels in 75 non-obese chronic hepatitis C (CHC) patients and 41 healthy controls similar in age and BMI; (2) the relationship between their serum concentration and insulin resistance, liver histology, and biochemical parameters; (3) their effectiveness as diagnostic markers. Results. FGF21 levels increased significantly in CHC patients compared with controls (p = 0.04). CHC patients with steatosis had significantly higher FGF21 levels compared with those without steatosis (p = 0.01). FGF21 concentration was positively related to steatosis grade (r = 0.39, p = 0.007). RBP4 levels did not differ between CHC patients and controls, but were negatively associated with necro-inflammatory activity grade (r = (-0.34), p = 0.04), with significantly higher levels in patients with minimal inflammatory activity (G1 vs. G2/3, p < 0.001; G1 vs. G2, p = 0 < 001; G1 vs. G3, p = 0.01). After stepwise linear regression analysis adjusting for potential confounders, RBP4 levels retained their independent significance as a predictor of necro-inflammatory activity (β = -0.31; t = -2.15, p = 0.035) and FGF21 levels as a predictor of steatosis (β = 0.34; t = 2.31, p = 0.024). Serum FGF21 correlated with serum RBP4 levels (r = 0.32, p = 0.02). Conclusions. Serum FGF21 levels increased in CHC patients, especially in those with steatosis and were associated with steatosis grade. FGF21 seems to be a useful diagnostic marker in determining hepatic steatosis in CHC. A negative association between serum RBP4 and necro-inflammatory activity indicates that disease severity may determine RBP4 levels.