Band 30, Heft 2 - SPECIAL ISSUE: THE HORMONE FGF 21: A PARAMOUNT ACTOR OF ENDOCRINE METABOLIC REGULATION, AND EVEN MORE / Editors: Gérard S. Chetrite and Bruno Fève - continued

Fibroblast growth factor 21 (FGF21) analogs and FGF21 receptor agonists (FGF21RAs) that mimic FGF21 ligand activity constitute the new “FGF21-class” of anti-obesity and anti-diabetic molecules that improve insulin sensitivity, ameliorate hepatosteatosis and promote weight loss. The metabolic actions of FGF21-class proteins in obese mice are attributed to stimulation of brown fat thermogenesis and increased secretion of adiponectin. The therapeutic utility of this class of molecules is being actively investigated in clinical trials for the treatment of type 2 diabetes and non-alcoholic steatohepatitis (NASH). This review is focused on various FGF21-class molecules, their molecular designs and the preclinical and clinical activities. These molecules include modified FGF21 as well as agonistic antibodies against the receptor for FGF21, namely the complex of FGF receptor 1 (FGFR1) and the obligatory coreceptor βKlotho (KLB). In addition, a novel approach to increase endogenous FGF21 activity by inhibiting the FGF21-degrading protease fibroblast activation protein (FAP) is discussed.

Fibroblast growth factor 21 (FGF21) plays a role in regulating adaptation to various metabolic abnormalities. In addition, FGF21 is involved in controlling glucose and lipid homeostasis. The regulation of FGF21 is a complex process and depends upon multiple metabolic factors and hormones. Humans and animals with obesity or type 2 diabetes have abnormal expression and changes of FGF21 in the circulation. Interventional studies in rodents and monkeys with obesity, insulin resistance or type 2 diabetes revealed a potential therapeutic relevance of FGF21 in correcting these abnormalities. This review summarizes the current knowledge about the regulation of FGF21 by distinct metabolic and endogenous factors, considering the most relevant studies. In this context, the results of interventional studies in humans and various animal models of diseases, such as diabetes and obesity, are discussed. In addition, potential mechanisms of the molecular regulation of FGF21 expression and secretion are reviewed.

Fibroblast growth factor 21 (FGF21) is a newly discovered adipokine, synthesized by several organs, mostly by the liver, which was introduced as a potent metabolic regulator and insulin-sensitizing factor. Numerous animal studies have demonstrated that FGF21 improves glucose and lipids metabolism and exerts anti-inflammatory effects. However, data obtained from human studies have shown contradictory results, in which circulating FGF21 levels were often elevated in obesity, dyslipidemia, type 2 diabetes (DM2) and other conditions connected with insulin resistance. This increase in basal FGF21 concentrations observed in patients with obesity and other conditions related to insulin resistance was being explained as a compensatory response to the underlying metabolic disturbances or tissue resistance to FGF21 action. Furthermore, the results of clinical trials have shown that increased FGF21 concentrations were associated with increased cardiovascular (CV) risk and had a prognostic value in CV outcomes. In recent years, it has been reported that FGF21 may exert cardioprotective effects. This mini-review aims to summarize the current state of knowledge about the role of FGF21 in CV disorders, and discuss the molecular mechanism underlying the anti-atherogenic properties of this compound.

Fibroblast growth factor-21 (FGF21), produced mainly in hepatocytes and adipocytes, promotes leanness, insulin sensitivity, and vascular health while down-regulating hepatic IGF-I production. Transgenic mice overexpressing FGF21 enjoy a marked increase in median and maximal longevity comparable to that evoked by calorie restriction – but without a reduction in food intake. Transcriptional factors which promote hepatic FGF21 expression include PPARα, ATF4, STAT5, and FXR; hence, fibrate drugs, elevated lipolysis, moderate-protein vegan diets, growth hormone, and bile acids may have potential to increase FGF21 synthesis. Sirt1 activity is required for optimal responsiveness of FGF21 to PPARα, and Sirt1 activators can boost FGF21 transcription. Conversely, histone deacetylase 3 (HDAC3) inhibits PPARα’s transcriptional impact on FGF21, and type 1 deacetylase inhibitors such as butyrate therefore increase FGF21 expression. Glucagon-like peptide-1 (GLP-1) increases hepatic expression of both PPARα and Sirt1; acarbose, which increases intestinal GLP-1 secretion, also increases FGF21 and lifespan in mice. Glucagon stimulates hepatic production of FGF21 by increasing the expression of the Nur77 transcription factor; increased glucagon secretion can be evoked by supplemental glycine administered during post-absorptive metabolism. The aryl hydrocarbon receptor (AhR) has also been reported recently to promote FGF21 transcription. Bilirubin is known to be an agonist for this receptor, and this may rationalize a recent report that heme oxygenase-1 induction in the liver boosts FGF21 expression. There is reason to suspect that phycocyanorubin, a bilirubin homolog that is a metabolite of the major phycobilin in spirulina, may share bilirubin’s agonist activity for AhR, and perhaps likewise promote FGF21 induction. In the future, regimens featuring a plant-based diet, nutraceuticals, and safe drugs may make it feasible to achieve physiologically significant increases in FGF21 that promote metabolic health, leanness, and longevity.

Background: Fibroblast growth factor 21 (FGF-21) is a hepatic protein that plays a critical role in liver, adipose tissue, and bone metabolism. Animal models reported an increase of FGF-21 and associated growth disturbances in undernutrition. Therefore, we studied the impact of weight loss in obese children on growth, FGF-21, and insulin-like factor 1 (IGF-1) concentrations. Methods: We analyzed height, serum concentrations of FGF-21, IGF-1, IGFBP-3, leptin, and insulin at baseline and 1 year later in 30 obese children with substantial weight loss (reduction >0.5 BMI-SDS) and in 30 obese children of similar age, gender, and pubertal stage with stable BMI-SDS. All children participated in a 1-year lifestyle intervention. Height and IGF-1 was transformed to standard deviation score (SDS). Multiple linear regression analyses adjusted for age, gender, and pubertal stage were performed. Results: At baseline, height-SDS was significantly related to IGF-1-SDS (β-coefficient 0.68 95% confidence interval (95% CI)±0.49; p=0.008) and leptin (β-coefficient 0.042 95% CI±0.030; p=0.008), but not to FGF-21 or insulin. FGF-21 was not significantly associated with IGF-1 or IGFBP-3. In longitudinal analysis, changes of FGF-21 were not significantly related to changes of height, IGF-1-SDS or IGFBP-3. However, in the subgroup of 30 children with substantial BMI-SDS reduction, FGF-21, leptin, insulin, and HOMA decreased significantly. Conclusion: As there was no significant association between FGF-21 and growth or IGF-1 both in cross-sectional and longitudinal analyses, these findings do not support the hypothesis that FGF-21 is involved in growth of obese children. Further studies are necessary to understand the multiple alterations in the growth hormone (GH) axis in obese children.