Fibroblast growth factor 21 (FGF21) has been suggested to improve metabolism during aerobic exercise in obesity. However, the variability of exercise interventions gives rise to discrepancies in the field. Therefore, we aimed to systematically review the available literature regarding the effects of aerobic exercise on FGF21 in the context of overweight and obesity. Our search included original articles published between 2009 and November 2021 found in PubMed, Science Direct, and Medline. Clinical and preclinical studies were included. Studies, where subjects or animals presented with other conditions (e.g., cancer, stroke), were excluded. From an initial 43 studies, 19 (clinical studies = 9; preclinical studies = 10) were eligible for inclusion in this review. The main findings were that acute exercise tended to increase circulatory levels of FGF21. In contrast, chronic exercise programs (≥4 weeks) had the opposite effect along with inducing mRNA and protein increases of FGF receptors and β-klotho in adipose tissue, liver, and skeletal muscle. In conclusion, both clinical and preclinical studies showed that aerobic exercise exerts changes in circulatory and tissue FGF21, along with its receptors and co-receptor. Future research is needed to elucidate the mechanisms, along with the physiological and clinical implications of these changes.

Background: The association between fibroblast growth factor 21 (FGF21) and cardiovascular disease (CVD) risk remains unclear. We conducted this systematic review and meta-analysis to evaluate the association between FGF21 and CVDs, and relevant vascular parameters. Methods: PubMed and Web of Science databases were systematically searched to identify relevant studies published before March 2021. The FGF21 concentration was compared between individuals with and without CVDs. The effect of FGF21 on CVD risk was assessed by using hazard ratio (HR) and odds ratio (OR). The association between FGF21 and vascular parameters was assessed by Pearson\'s r. Study quality was assessed using Newcastle-Ottawa Scale and Joanna Briggs Institution Checklist. Results: A total of 29,156 individuals from 30 studies were included. Overall, the serum FGF21 concentration was significantly higher in CVD patients (p < 0.001), especially for coronary artery disease (CAD) (p < 0.001) and hypertension (p < 0.001). The pooled OR (p = 0.009) and HR (p < 0.001) showed that the risk of CVDs increased with FGF21. The linear association between FGF21 and vascular parameters, including pulse wave velocity (r = 0.32), carotid intima-media thickness (r = 0.21), ankle-brachial index (r = 0.33), systolic blood pressure (r = 0.13), and diastolic blood pressure (r = 0.05), was insignificant. The incidence of overall CVDs (p = 0.03) was significantly higher in individuals with higher FGF21 levels. Conclusion: High-level serum FGF21 concentration is closely associated with an increased risk of CVDs, which may be independent of vascular parameters. A standard FGF21 classification threshold needs to be established before clinical use for CVD risk assessment. Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=241968, identifier: CRD42021241968.

Vascular calcification (VC) is an independent cardiovascular event and also a complication commonly found in chronic kidney disease (CKD) and diabetic patients. The mechanisms underpinning pathophysiology of VC is yet to be fully understood. Nevertheless, certain processes are generally believed to participate in its onset and progression. VC pathology is characterized by disequilibrium in the amount of natural inhibitors and active inducers of VC process. The imbalance may favor ectopic deposition of calcium-phosphate in form of hydroxyapatite in media or intima tunica compartments of blood vessels. This eventually could trigger phenotypic switch of smooth muscle cells to osteoblasts related cells. Thus, VSMC phenotypic trans-differentiation is currently considered as one of the hallmarks of VC. At the moment, there is no approved treatment. Fibroblast growth factors (FGFs) are a protein family that participates in varieties of biological processes. More recently, FGF21 seems to be gaining more attention with recent findings showing its anti-calcifying efficacy. In this review, the aim is to point out specific processes involved in VC and also to highlight the participation of FGF21 in the pathology of vascular calcification.

OBJECTIVE: Fibroblast growth factor-21 (FGF-21) plays an important role in glucose and lipid metabolism. This study aims to systemically review the evidence regarding the relationship between the FGF-21 levels and type 2 diabetes mellitus (T2DM), as well as the related influential factors.
METHODS: Research related to plasma/serum FGF-21 levels in patients with T2DM and healthy controls were searched in PubMed, EMBASE and The Cochrane Library databases (up to 31 March 2017). Pooled standard mean difference (SMD) with 95% CI was calculated by fixed-effect or random-effect model analysis. Heterogeneity test was performed by the Q-statistic and quantified using I 2, and publication bias was evaluated using a funnel plot and Egger\'s linear regression test.
RESULTS: In total, 317 articles were obtained after searching databases, and 11 studies with 866 patients with T2DM and 629 controls were finally included. Meta-analysis revealed that, compared with the control group, the T2DM group had a significantly higher plasma/serum FGF-21 level (p < 0.001), with the SMD of 1.34% and 95% CI (0.70 to 1.98). Meta-regression analysis and subgroup analyses suggested that body mass index (BMI), triglycerides (TG) and total cholesterol (TC) were likely related to the observed FGF-21 differences between two groups.
CONCLUSIONS: Overall, our study suggests that patients with T2DM have significantly higher plasma/serum FGF-21 levels, and the FGF-21 levels were influenced by BMI, TC and TG.

Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset or first diagnosis during pregnancy, but not to the level of being diagnostic for diabetes in a nonpregnant adult. In GDM, whole-body insulin-dependent glucose disposal decreases by 40%-60% which necessitates a 200%-250% increase in insulin secretion to maintain normoglycaemia. GDM develops when a pregnant woman does not produce sufficient insulin to compensate for the reduced glucose disposal. Fibroblast growth factor 21 (FGF21) is a hormone that is expressed predominantly in the liver, but also in other metabolically active tissues such as pancreas, skeletal muscle and adipose tissue. In animals, FGF21 lowers blood glucose levels and inhibits glucagon secretion. In humans, circulating FGF21 levels are increased in insulin-resistant morbidities such as obesity and type 2 diabetes mellitus (T2DM). An elevated FGF21 level is also an independent predictor of T2DM. GDM and T2DM are proposed to have similar underlying pathophysiologies, raising the question of whether a similar relationship exists between FGF21 and GDM as it does with T2DM. There are a limited number of studies investigating FGF21 levels in patients with GDM. Moreover, recent clinical trials investigating the therapeutic potential of FGF21 have highlighted a major gap in our understanding of the biology of FGF21. This review evaluates what is currently known about FGF21 and GDM and highlights important gaps that warrant further research.

Diabetes mellitus (DM) is a major endocrine metabolic disease and is marked by a lack of insulin. The complication of DM is one of the most difficult problems in medicine. The initial translational studies revealed that growth factors have a major role in integrating tissue physiology and in embryology as well as in growth, maturation and tissue repair. In some tissues affected by diabetes, growth factors are induced by a relative deficit or excess. Fibroblast growth factor 21 (FGF21) is a promising regulator of glucose and lipid metabolism with multiple beneficial effects including hypoglycemic and lipid-lowering. Vascular endothelial growth factor (VEGF) is a potent angiogenic and vascular permeability factor and is implicated in both of these complications in diabetes. Increase or decrease in the production of transforming growth factor-β1 (TGF-β1) has been associated with diabetic nephropathy and retinopathy. The insulin-like growth factor-I (IGF-I) is a naturally-occurring single chain polypeptide which has been widely used in the treatment of diabetic glomerular and renal tubular injuries. This review summarizes the recent evidences for an involvement of growth factors in diabetic complications, focusing on their emergence in sequence of events leading to vascular complications or their potential therapeutic role in these diseases. Growth factor therapy in diabetic foot ulcers is already a clinical reality. As methods to finely regulate growth factors in a tissue and time-specific manner are further developed and tested, regulation of the growth factor to normal level in vivo may well become a therapy to prevent and treat diabetic complications.

Fibroblast growth factor 21 is a signalling protein involved in cell differentiation, morphogenesis, proliferation and metabolism. Recent studies have associated increased levels of FGF21 in the development of cardiovascular diseases, whereas others have reported no significant associations. Therefore, this systematic review and meta-analysis evaluated the value in predicting the risk of cardio-metabolic disorders and mortality.
PubMed and EMBASE were searched until 5th September 2017 for studies that evaluated the roles of FGF21 levels in cardio-metabolic disorders.
A total of 183 and 301 entries were retrieved; 24 studies met the inclusion criteria. Four studies were identified by an additional search. Therefore, 28 studies were included in the final meta-analysis. High FGF21 levels significantly predicted the incidence of coronary artery disease (hazard ratio [HR]: 1.29; 95% confidence interval [CI]: 1.06-1.55; P < 0. 01; I2 = 48%) and the risk of metabolic syndrome (HR: 1.70, 95% CI: 1.35-2.15; P < 0.0001 I2 = 24%). In diabetes mellitus, FGF21 predicted disease incidence or progression (HR: 1.35, 95% CI: 1.06-1.72, P < 0.05, I2 = 69%) and worsening renal failure (HR: 1.06, 95% CI: 1.03-1.09, P < 0.0001, I2 = 47%). FGF21 also predicted all-cause mortality (HR: 3.00, 95% CI: 1.23-7.33; P < 0.05; I2 = 51%), and cardiovascular mortality (HR: 2.33, 95% CI: 1.08-4.99, P < 0.05, I2 = 75%).
FGF21 significantly predicts the incidence of coronary artery disease, the risks of metabolic syndrome, diabetes mellitus and renal progression in diabetes. It also predicted all-cause and cardiovascular mortality.

Achondroplasia (ACH) occurs in most cases as de novo mutations of the gene-encoding fibroblast growth factor receptor 3 (FGFR3). Biliary atresia (BA) is a progressive neonatal inflammatory and fibro-obliterative cholangiopathy affecting the extra- and intrahepatic biliary tree to varying degrees, and it results in obstruction to bile flow and cholestatic jaundice in neonates. BA is thought to be a multifactorial disease, genome association studies have shown abnormalities in susceptibility genes, and levels of fibroblast growth factor 21 (FGF21) and fibroblast growth factor 23 (FGF23) have been noted to be increased. These two conditions occurring in the same patient has never been reported before.

Fibroblast growth factor 21 (FGF21) has been well-recognized as a metabolic hormone and a promising target for treatment of metabolic diseases. The level of endogenous FGF21 is elevated in patients with impaired glucose tolerance and progressively increased from patients with overt type 2 diabetes to those with micro- and macro-vascular complications, presumably as a compensation or response to the deterioration of metabolic imbalance. A few exploratory in vivo studies, including a recent clinical trial, showed that exogenous FGF21 mimetics targeting FGF21 signaling can attain beneficial metabolic effects not with-standing the already elevated ambient FGF21 levels. In addition, some clinically available pharmacologic agents such as fenofibrates and metformin may modulate energy and macronutrients metabolism by acting through FGF21. This review mainly focuses on the role of FGF21 in development, progression and treatment of type 2 diabetes from a clinical perspective.