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Aims/Introduction To explore the differences of serum fibroblast growth factor‐21 (FGF‐21) levels in pregnant women with normal glucose tolerance and gestational diabetes mellitus (GDM), and to analyze the relationship between FGF‐21 and glucose and lipid metabolic indicators, leptin, retinol binding protein 4 (RBP‐4) and adiponectin in GDM, in order to provide basis for the prevention and treatment of GDM. Materials and Methods Total of 120 women were included, and divided into normal glucose tolerance group (58 cases) and GDM group (62 cases) according to the 75 g oral glucose tolerance test results. General information were recorded; height, weight and blood pressure, blood glucose, lipids, insulin, FGF‐21, leptin, RMP‐4, and adiponectin were measured, and body mass index (BMI), homeostasis model assessment‐IR, homeostasis model assessment‐β and area under glucose curve were calculated. The t‐test, Pearson analysis and multiple linear regression analysis were used to evaluate the differences and related factors of FGF‐21 in GDM. Results The pre‐pregnancy BMI, pregnancy BMI, weight gain during pregnancy and FGF‐21 levels were higher in GDM group, whereas there were no statistically significant differences in leptin, RBP‐4 and adiponectin. Correlation analysis suggested that FGF‐21 level was correlated with age, pre‐pregnancy BMI, weight gain during pregnancy, high‐density lipoprotein cholesterol, leptin, RBP‐4 and adiponectin, and the results of multiple linear regression showed that serum FGF‐21 was related to pre‐pregnancy BMI, weight gain during pregnancy, leptin, RBP‐4 and adiponectin in GDM. Conclusions There were higher serum FGF‐21 levels in GDM, which might be related to pre‐pregnancy BMI, weight gain during pregnancy, leptin, RBP‐4 and adiponectin. The relationship between serum adipokine fibroblast growth factor‐21 (FGF‐21) and gestational diabetes mellitus (GDM). A total of 120 female patients were divided into normal glucose test (NGT) group (n = 58) and GDM group (n = 62) according to their oral glucose tolerance test (OGTT) results. Multivariable linear regression showed that serum FGF‐21 was related to pre‐pregnancy body mass index (BMI), weight gain during pregnancy, leptin, retinol binding protein 4 (RBP‐4) and adiponectin in GDM.

Background： Chronic kidney disease （CKD） is closely related to the cardiovascular events in vascular calcification （VC）. However, little has known about the characteristics of kidney injury caused by VC. Fibroblast growth factor 21 （FGF21 ） is an endocrine thctor, which takes part in various metabolic actions with the potential to alleviate metabolic disorder diseases, Even FGF21 has been regarded as a biomarker in CKD, the role of FGF21 in CKD remains unclear. Therefore, in this study, we evaluate the FGF21 on the kidney injury in VC rats. Methods： The male Sprague-Dawley rats were divided into three groups： （ 1 ） control group, （2） Vitamin D3 plus nicotine （VDN）-induced VC group, （3） FGF21-treated VDN group. After 4 weeks, the rats were killed and the blood was collected for serum creatinine, urea nitrogen, calcium, and phosphate measurement. Moreover, the renal tissues were homogenized for alkaline phosphatases （ALPs） activity and calcium content. The levels of FGF21 protein were measured by radioimmunoassay. The levels of β-Klotho and FGF receptor 1 （FGFR1） protein were measured by enzyme-linked immunosorbent assay （EL1SA）. The structural damage and calcifications in aortas were stained by Alizarin-red S. Moreover, the structure of kidney was observed by hematoxylin and eosin staining. Results： The renal lhnction impairment caused by VDN modeling was ameliorated by FGF21 treatment, inhibited the elevated serum creatinine and urea level by 20.5% （34.750 ± 4.334 pmol/L vs. 27.630± 2.387pamol/L） and 4.0% （7.038 ± 0.590 mmol/L vs. 6.763 ±0.374 mmol/L; P 〈 0.01 ）, respectively, together with the structural damages of glomerular atrophy and renal interstitial fibrosis. FGF21 treatment downregulated the ALP activity, calcium content in the kidney of VC rats by 42.1% （P 〈 0.01 ） and 11.7% （P 〈 0.05） as well as ameliorated the aortic injury and calcification as compared with VDN treatment alone group, indicating an ameliorative effect on VC. EL1SA assays showed that the expression of [3-Klotho, a component of FGF21 receptor system was increased in VDN-treated VC rats by 37.4% （6.588 ± 0.957 pg/mg vs. 9.054 ± 0.963 pg/mg; P 〈 0.01）, indicating an FGF2 l-resistant state. Moreover, FGF21 treatment downregulated the level of β-Klotho in renal tissue by 16.7% （9.054 ± 0.963 pg/mg vs. 7.544± 1.362 pg/mg, P 〈 0.05）. However, the level of FGFR1, the receptor of FGF21, kept unchanged under VDN and VDN plus FGF21 administration （0.191 ± 0.0376 rig/rag vs. 0.189 ± 0.032 ng/mg rs. 0.181± 0.034 mg/mg; P 〉 0.05）. Conclusions： In the present study, FGF21 was observed to ameliorate the kidney injury in VDN-induced VC rats. FGF21 might be a potential therapeutic factor in CKD by cutting offthe vicious circle between VC and kidney injury.

Background The objective of this study is to investigate the effects of a low-protein diet (LPD) starting from a young age on diabetic status and renal injury in a rat model of type 2 diabetes and obesity. Methods Diabetic male Wistar fatty ( fa/fa ) rats (WFRs) were fed a standard diet (23.84% protein) or an LPD (5.77% protein) for 24 weeks beginning at 6 weeks of age. We investigated the effects of the LPD on total body weight (BW); fat weight (FW); lower-limb muscle weight (MW); several measures of diabetic status, including fasting/random glucose levels, HOMA-IR and the IPITT; and renal injuries, including renal hypertrophy, albuminuria and histological changes. Additionally, autophagy and activation of mTORC1 were evaluated in the diabetic renal cortex. Furthermore, plasma FGF21 and high-molecular-weight (HMW) adiponectin levels, as well as UCP1 expression levels in brown adipose tissue (BAT), were evaluated. Results Increases in BW and FW in WFRs were significantly reduced by the LPD, and the LPD resulted in a significant reduction of lower-limb MW in WFRs. The LPD suppressed the elevation of glucose levels in WFRs through improvement of insulin resistance. The LPD also elevated the plasma FGF21 and HMW adiponectin of WFRs, as well as UCP1 expression in the BAT of the animals. Renal hypertrophy, albuminuria, renal histological changes, and increased expression of p62 and phospho-S6 ribosomal protein (p-S6RP) were observed in WFRs compared with the values from WLRs. The LPD clearly prevented the diabetic kidneys from sustaining any damage. Conclusions The LPD prevented the progression of diabetic status; this effect may have been associated with the reduction of FW and the elevation of plasma FGF21 and HMW adiponectin, as well as UCP1 expression in BAT, resulting in suppression of diabetic nephropathy. However, MW was decreased in rats by the consumption of an LPD from a young age; therefore, further research is needed to resolve the nutritional issue of LPD on decreasing in MW.

Exercise training has been reported to alleviate cardiac fibrosis and ameliorate heart dysfunction after myocardial infarction (MI), but the molecular mechanism is still not fully clarified. Fibroblast growth factor 21 (FGF21) exerts a protective effect on the infarcted heart. This study investigates whether exercise training could increase FGF21 protein expression and regulate the transforming growth factor-β1 (TGF-β1)-Smad2/3-MMP2/9 signaling pathway to alleviate cardiac fibrosis following MI. Male wild type (WT) C57BL/6J mice and Fgf21 knockout (Fgf21 KO) mice were used to establish the MI model and subjected to five weeks of different types of exercise training. Both aerobic exercise training (AET) and resistance exercise training (RET) significantly alleviated cardiac dysfunction and fibrosis, up-regulated FGF21 protein expression, inhibited the activation of TGF-β1-Smad2/3-MMP2/9 signaling pathway and collagen production, and meanwhile, enhanced antioxidant capacity and reduced cell apoptosis in the infarcted heart. In contrast, knockout of Fgf21 weakened the cardioprotective effects of AET after MI. In vitro, cardiac fibroblasts (CFs) were isolated from neonatal mice hearts and treated with H2O2 (100 μM, 6 h). Recombinant human FGF21 (rhFGF21, 100 ng/mL, 15 h) and/or 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR, 1 mM, 15 h) inhibited H2O2-induced activation of the TGF-β1-Smad2/3-MMP2/9 signaling pathway, promoted CFs apoptosis and reduced collagen production. In conclusion, exercise training increases FGF21 protein expression, inactivates the TGF-β1-Smad2/3-MMP2/9 signaling pathway, alleviates cardiac fibrosis, oxidative stress, and cell apoptosis, and finally improves cardiac function in mice with MI. FGF21 plays an important role in the anti-fibrosis effect of exercise training.

Diabetic cardiomyopathy (DCM) in type 2 diabetes (T2D) may lead to heart failure and patient death. Fibroblast growth factor 21 (FGF21) is a therapeutic candidate for treating this disease. However, one impediment to its clinical use is its weak ability to activate downstream signaling pathways. In this study, based on our in-depth understanding of the binding properties of fibroblast growth factor receptor 1c (FGFR1c) with paracrine FGF1 and endocrine FGF21, we engineered a novel FGF21 analog named FGF21D2D3. This was achieved by substituting the R96–V106 region of FGF21 (the binding site with the D2–D3 domain of FGFR1c) with the corresponding region from FGF1. Structural characterization and binding affinity tests showed that the analog’s capacity to bind FGFR1c was significantly enhanced compared to wild-type FGF21 (FGF21WT). In a T2D mouse model, we found that FGF21D2D3 had greater potency than FGF21WT in improving hyperlipidemia and DCM. Furthermore, mechanistic studies revealed that FGF21D2D3 more effectively bound FGFR1, activated AMPK, inhibited oxidative stress, and ameliorated DCM. Therefore, our data indicate that FGF21D2D3 is a better substitute for FGF21WT in treating DCM by improving dyslipidemia and directly suppressing oxidative stress via FGFR1–AMPK activation in T2D.

Cardiovascular and metabolic disease (CVMD) is becoming increasingly prevalent in developed and developing countries with high morbidity and mortality. In recent years, fibroblast growth factor 21 (FGF21) has attracted intensive research interest due to its purported role as a potential biomarker and critical player in CVMDs, including atherosclerosis, coronary artery disease, myocardial infarction, hypoxia/reoxygenation injury, heart failure, type 2 diabetes, obesity, and nonalcoholic steatohepatitis. This review summarizes the recent developments in investigating the role of FGF21 in CVMDs and explores the mechanism whereby FGF21 regulates the development of CVMDs. Novel molecular targets and related pathways of FGF21 (adenosine 5'-monophosphate-activated protein kinase, silent information regulator 1, autophagy-related molecules, and gut microbiota-related molecules) are highlighted in this review. Considering the poor pharmacokinetics and biophysical properties of native FGF21, the development of new generations of FGF21-based drugs has tremendous therapeutic potential. Related preclinical and clinical studies are also summarized in this review to foster clinical translation. Thus, our review provides a timely and insightful overview of the physiology, biomarker potential, molecular targets, and therapeutic potential of FGF21 in CVMDs.

Accumulating studies suggest that overnutrition-associated obesity may lead to development of type 2 diabetes mellitus and metabolic syndromes (MetS). MetS and its components are important risk factors of mild cognitive impairment, age-related cognitive decline, vascular dementia, and Alzheimer’s disease. It has been recently proposed that development of a disease-course modification strategy toward early and effective risk factor management would be clinically significant in reducing the risk of metabolic disorder-initiated cognitive decline. In the present study, we propose that fibroblast growth factor 21 (FGF21) is a novel candidate for the disease-course modification approach. Using a high-fat diet (HFD) consumption-induced obese mouse model, we tested our hypothesis that recombinant human FGF21 (rFGF21) administration is effective for improving obesity-induced cognitive dysfunction and anxiety-like behavior, by its multiple metabolic modulation and anti-pro-inflammation actions. Our experimental findings support our hypothesis that rFGF21 is protective to HFD-induced cognitive impairment, at least in part by metabolic regulation in glucose tolerance impairment, insulin resistance, and hyperlipidemia; potent systemic pro-inflammation inhibition; and improvement of hippocampal dysfunction, particularly by inhibiting pro-neuroinflammation and neurogenesis deficit. This study suggests that FGF21 might be a novel molecular target of the disease-course-modifying strategy for early intervention of MstS-associated cognitive decline.

Most studies regarding the beneficial effect of sulforaphane (SFN) on non-alcoholic fatty liver disease (NAFLD) have focused on nuclear factor E2-related factor 2 (Nrf2). But the molecular mechanisms underlying the beneficial effect of SFN in the treatment of NAFLD remain controversial. Fibroblast growth factor (FGF) 21 is a member of the FGF family expressed mainly in liver but also in adipose tissue, muscle and pancreas, which functions as an endocrine factor and has been considered as a promising therapeutic candidate for the treatment of NAFLD. In the present study we investigated whether FGF21 was involved in the therapeutic effect of SFN against NAFLD. C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to generate NAFLD and continued on the HFD for additional 6 weeks with or without SFN treatment. We showed that administration of SFN (0.56 g/kg) significantly ameliorated hepatic steatosis and inflammation in NAFLD mice, along with the improved glucose tolerance and insulin sensitivity, through suppressing the expression of proteins responsible for hepatic lipogenesis, while enhancing proteins for hepatic lipolysis and fatty acids oxidation. SFN administration significantly increased hepatic expression of FGFR1 and fibroblast growth factor 21 (FGF21) in NAFLD mice, along with decreased phosphorylation of p38 MAPK (the downstream of FGF21). HepG2 cells were treated in vitro with FFAs (palmitic acid and oleic acid) followed by different concentrations of SFN. We showed that the effects of SFN on FGF21 and FGFR1 protein expression were replicated in FFAs-treated HepG2 cells. Moreover, the increased FGFR1 protein occurred earlier than increased FGF21 protein. Interestingly, the rapid effect of SFN on FGFR1 protein was not regulated by the FGFR1 gene transcription. Knockdown of FGFR1 and p38 genes weakened SFN-reduced lipid deposition in FFAs-treated HepG2 cells. SFN administration in combination with rmFGF21 (1.5 mg/kg, i.p., every other day) for 3 weeks further suppressed hepatic steatosis in NAFLD mice. In conclusion, SFN ameliorates lipid metabolism disorders in NAFLD mice by upregulating FGF21/FGFR1 pathway. Our results verify that SFN may become a promising intervention to treat or relieve NAFLD.

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin‐releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 ( FGFR1 ) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with β‐Klotho (KLB), the obligate co‐receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH. Genetic screening of 334 CHH patients identified seven heterozygous loss‐of‐function KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction. Synopsis Defects in FGF21/KLB/FGFR1 signaling contribute to GnRH deficiency in both humans and mice. This signaling pathway is a novel link between metabolism and reproduction. Heterozygous loss‐of‐function mutations in KLB are found in patients with congenital hypogonadotropic hypogonadism. Klb ‐deficient mice delayed sexual maturation and impaired fertility with decreased gonadotropins due to a hypothalamic defect. Klb is expressed in the postnatal hypothalamus including GnRH neurons. FGF21 reaches GnRH neurons via fenestrated capillaries in the hypothalamus in vivo and enhances GnRH release in median eminence explants in vitro . Graphical Abstract Defects in FGF21/KLB/FGFR1 signaling contribute to GnRH deficiency in both humans and mice. This signaling pathway is a novel link between metabolism and reproduction.

Aims/hypothesis This study investigated fibroblast growth factor 21 (FGF21)-mediated cardiac protection against apoptosis caused by diabetic lipotoxicity and explored the protective mechanisms involved. Methods Cardiac Fgf21 mRNA expression was examined in a diabetic mouse model using real-time PCR. After pre-incubation of palmitate-treated cardiac H9c2 cells and primary cardiomyocytes with FGF21 for 15 h, apoptosis and Fgf21 -induced cell-survival signalling were investigated using small interfering (si)RNA and/or pharmacological inhibitors. We also examined the cardiac apoptotic signalling and structural and functional indices in wild-type and Fgf21 -knockout ( Fgf21 -KO) diabetic mice. Results In a mouse model of type 1 diabetes, cardiac Fgf21 expression was upregulated about 40-fold at 2 months and 3–1.5-fold at 4 and 6 months after diabetes. FGF21 significantly reduced palmitate-induced cardiac apoptosis. Mechanistically, palmitate downregulated, but FGF21 upregulated, phosphorylation levels of extracellular signal-regulated kinase (ERK)1/2, mitogen-activated protein kinase 14 (p38 MAPK) and AMP-activated protein kinase (AMPK). Inhibition of each kinase with its inhibitor and/or siRNA revealed that FGF21 prevents palmitate-induced cardiac apoptosis via upregulating the ERK1/2-dependent p38 MAPK–AMPK signalling pathway. In vivo administration of FGF21, but not FGF21 plus ERK1/2 inhibitor, to diabetic or fatty-acid-infused mice significantly prevented cardiac apoptosis and reduced inactivation of ERK1/2, p38 MAPK and AMPK and prevented cardiac remodelling and dysfunction. The Fgf21 -KO mice were more susceptible to diabetes-induced cardiac apoptosis, and this could be prevented by administration of FGF21. Deletion of Fgf21 did not further exacerbate cardiac dysfunction. Conclusions/interpretation These results demonstrate that FGF21 prevents lipid- or diabetes-induced cardiac apoptosis by activating the ERK1/2–p38 MAPK–AMPK pathway. FGF21 may be a therapeutic target for the treatment of diabetes-related cardiac damage.