Fibroblast Growth Factor 21 Expression Research Articles

Aortic Injury Induced by Benzo(a)pyrene and Atherogenic Diet Increased Hepatic FGF21 Expression in C57BL/6J Mice

Background: Benzo(a)pyrene (BaP), an environmental toxicant and endocrine disruptor, has been shown to exacerbate atherosclerosis when combined with a high-fat diet. Fibroblast Growth Factor-21 (FGF21), a novel hormone with anti-atherosclerotic properties, is associated with the presence of atherosclerosis and reduces plaque formation in experimental animals. Objectives: The present study aimed to investigate the chronic effect of BaP injection on hepatic FGF21 expression, as an anti-atherosclerotic hormone, in mice fed with or without an atherogenic diet (AtD). Methods: Eighteen C57BL/6J male mice (6 weeks) were randomly divided into six groups based on the dosage and diet. Blood samples were collected, and serum cholesterol, triglyceride, HDL-C, LDL-C, and glucose levels were measured. FGF21 expression was assessed by quantitative real-time PCR. Atherosclerotic lesions in mice were studied with Oil Red O (ORO) staining. Results: Benzo(a)pyrene causes a significant increase in liver FGF21 expression in a dose-dependent manner, and BaP co-exposure with AtD leads to a further increase in FGF21 expression. Additionally, the addition of BaP to AtD significantly increased the serum glucose, cholesterol, and LDL-C levels and accelerated the formation of atherosclerotic lesions. Besides, our findings showed that there is a significant positive correlation between FGF21 expression and glucose, cholesterol, LDL-C, and ORO-positive areas. Conclusions: Our findings revealed that BaP increases the expression of endogenous FGF21 in treated animals as a compensatory response to protect the heart from atherosclerosis induced by BaP and AtD.

Causal relationship between inflammatory proteins and glioblastoma: a two-sample bi‑directional mendelian randomization study.

Background: Observational studies have indicated a potential correlation between glioblastoma and circulating inflammatory proteins. Further investigation is required to establish a causal relationship between these two factors. Methods: We performed a Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary of 91 circulating inflammation-related proteins (N = 14,824) to assess their causal impact on glioblastoma. The GWAS summary data for glioblastoma included 243 cases and 287,137 controls. The inverse variance weighted (IVW) method was used as the primary analytical method to assess causality. Four additional MR methods [simple mode, MR-Egger, weighted median, and weighted mode] were used to supplement the IVW results. Furthermore, several sensitivity analyses were performed to assess heterogeneity, horizontal pleiotropy, and stability. Reverse MR analysis was also performed. glioblastoma transcriptomic data from The Cancer Genome Atlas (TCGA) were analyzed to validate the findings obtained through MR, while pathway and functional enrichment analyses were conducted to predict the potential underlying mechanisms. Results: Our findings from employing the inverse variance weighted method in our forward MR analysis provide robust evidence supporting a potential association between glioblastoma and elevated levels of Cystatin D, as well as decreased levels of fibroblast growth factor 21 (FGF21) in the circulation. Moreover, our reverse MR analysis revealed that glioblastoma may contribute to increased concentrations of C-X-C motif chemokine 9 (CXCL9) and Interleukin-33 (IL-33) in the bloodstream. Transcriptomic analysis showed that FGF21 expression was inversely associated with the risk of developing glioblastoma, whereas an increased risk was linked to elevated levels of CXCL9 and IL-33. Pathway and functional enrichment analyses suggested that Cystatin D might exert its effects on glioblastoma through intracellular protein transport, whereas FGF21 might affect glioblastoma via glucose response mechanisms. Conclusion: These results indicate that FGF21 is a significant factor in glioblastoma susceptibility. Glioblastoma also affects the expression of inflammatory proteins such as C-X-C motif chemokine 9 and Interleukin-33, providing new insights into the mechanisms of glioblastoma genesis and clinical research.

Impaired Fibroblast Growth Factor 21 (FGF21) Associated with Visceral Adiposity Leads to Insulin Resistance: The Core Defect in Diabetes Mellitus.

The Central nervous system (CNS) is the prime regulator of signaling pathways whose function includes regulation of food intake (consumption), energy expenditure, and other metabolic responses like glycolysis, gluconeogenesis, fatty acid oxidation, and thermogenesis that have been implicated in chronic inflammatory disorders. Type 2 diabetes mellitus (T2DM) and obesity are two metabolic disorders that are linked together and have become an epidemic worldwide, thus raising significant public health concerns. Fibroblast growth factor 21 (FGF21) is an endocrine hormone with pleiotropic metabolic effects that increase insulin sensitivity and energy expenditure by elevating thermogenesis in brown or beige adipocytes, thus reducing body weight and sugar intake. In contrast, during starvation conditions, FGF21 induces its expression in the liver to initiate glucose homeostasis. Insulin resistance is one of the main anomalies caused by impaired FGF21 signaling, which also causes abnormal regulation of other signaling pathways. Tumor necrosis factor alpha (TNF-α), the cytokine released by adipocytes and inflammatory cells in response to chronic inflammation, is regarded major factor that reduces the expression of FGF21 and modulates underlying insulin resistance that causes imbalanced glucose homeostasis. This review aims to shed light on the mechanisms underlying the development of insulin resistance in obese individuals as well as the fundamental flaw in type 2 diabetes, which is malfunctioning obese adipose tissue.

Glucosamine Enhancement of Learning and Memory Functions by Promoting Fibroblast Growth Factor 21 Production.

Fibroblast growth factor 21 (FGF21) plays a crucial role in metabolism and brain function. Glucosamine (GLN) has been recognized for its diverse beneficial effects. This study aimed to elucidate the modulation of FGF21 production by GLN and its impact on learning and memory functions. Using both in vivo and in vitro models, we investigated the effects of GLN on mice fed with a normal diet or high-fat diet and on mouse HT22 hippocampal cells, STHdhQ7/Q7 striatal cells, and rat primary cortical neurons challenged with GLN. Our results indicated that GLN promotes learning and memory functions in mice and upregulates FGF21 expression in the hippocampus, cortex, and striatum, as well as in HT22 cells, STHdhQ7/Q7 cells, and cortical neurons. In animals receiving GLN together with an FGF21 receptor FGFR1 inhibitor (PD173074), the GLN-enhanced learning and memory functions and induction of FGF21 production in the hippocampus were significantly attenuated. While exploring the underlying molecular mechanisms, the potential involvement of NF-κB, Akt, p38, JNK, PKA, and PPARα in HT22 and NF-κB, Akt, p38, and PPARα in STHdhQ7/Q7 were noted; GLN was able to mediate the activation of p65, Akt, p38, and CREB in HT22 and p65, Akt, and p38 in STHdhQ7/Q7 cells. Our accumulated findings suggest that GLN may increase learning and memory functions by inducing FGF21 production in the brain. This induction appears to be mediated, at least in part, through GLN's activation of the NF-κB, Akt, p38, and PKA/CREB pathways.

Effects of Saikosaponin-A on Insulin Resistance in Obesity: Computational and Animal Experimental Study.

Obesity is known to be associated with increased inflammation and dysregulated autophagy, both of which contribute to insulin resistance. Saikosaponin-A (SSA) has been reported to exhibit anti-inflammatory and lipid-lowering properties. In this research, we employed a combination of computational modeling and animal experiments to explore the effects of SSA. Male C57BL/6 mice were categorized into four groups: normal diet, high-fat diet (HFD), HFD + atorvastatin 10 mg/kg, and HFD + SSA 10 mg/kg. We conducted oral glucose and fat tolerance tests to assess metabolic parameters and histological changes. Furthermore, we evaluated the population of Kupffer cells (KCs) and examined gene expressions related to inflammation and autophagy. Computational analysis revealed that SSA displayed high binding affinity to tumor necrosis factor (TNF)-α, nuclear factor (NF)-κB, fibroblast growth factor 21 (FGF21), and autophagy-related 7 (ATG7). Animal study demonstrated that SSA administration improved fasting and postprandial glucose levels, homeostatic model assessment of insulin resistance (HOMA-IR) index, as well as triglyceride, free fatty acid, total cholesterol, low-density lipoprotein cholesterol (LDL-C)-cholesterol, and high-density lipoprotein cholesterol (HDL-C)-cholesterol levels in HFD-fed mice. Moreover, SSA significantly reduced liver weight and fat accumulation, while inhibiting the infiltration and M1 activation of KCs. At the mRNA level, SSA downregulated TNF-α and NF-κB expression, while upregulating FGF21 and ATG7 expression. In conclusion, our study suggests that SSA may serve as a therapeutic agent for addressing the metabolic complications associated with obesity. This potential therapeutic effect is attributed to the suppression of inflammatory cytokines and the upregulation of FGF21 and ATG7.

FGF21 protects against ischaemia reperfusion injury in normal and fatty livers.

Liver ischaemia/reperfusion (I/R) injury, which is an inevitable clinical problem of liver resection, liver transplantation and haemorrhagic shock. Fibroblast growth factor 21 (FGF21) was intimately coupled with multiple metabolic processes and proved to protect against apoptosis and inflammatory response in hepatocytes during hepatic I/R injury. However, the regulatory mechanisms of FGF21 in hepatic I/R injury remains unknown. Therefore, we hypothesize that FGF21 protects hepatic tissues from I/R injury. Blood samples were available from haemangiomas patients undergoing hepatectomy and murine liver I/R model and used to further evaluate the serum levels of FGF21 both in humans and mice. We further explored the regulatory mechanisms of FGF21 in murine liver I/R model by using FGF21-knockout mice (FGF21-KO mice) and FGF21-overexpression transgenic mice (FGF21-OE mice) fed a high-fat or ketogenic diet. Our results show that the circulating levels of FGF21 were robustly decreased after liver I/R in both humans and mice. Silencing FGF21 expression with FGF21-KO mice aggravates liver injury at 6 h after 75 min of partial liver ischaemia, while FGF21-OE mice display alleviated hepatic I/R injury and inflammatory response. Compared with chow diet mice, exogenous FGF21 decreases the levels of aminotransferase, histological changes, apoptosis and inflammatory response in hepatic I/R injury treatment mice with a high-fat diet. Meanwhile, ketogenic diet mice are not sensitive to hepatic I/R injury. The circulating contents of FGF21 are decreased during liver warm I/R injury and exogenous FGF21 exerts hepatoprotective effects on hepatic I/R injury. Thus, FGF21 regulates hepatic I/R injury and may be a key therapeutic target.

The natural compounds, Magnolol or Honokiol, promote adipose tissue browning and resist obesity through modulating PPARα/γ activity

Non-alcoholic fatty liver disease (NAFLD) is closely associated with the body's energy metabolism. A potential strategy to regulate energy metabolism, combat obesity, and reduce NAFLD is by enhancing adipocyte thermogenesis and increasing energy expenditure. In this study, our objective was to examine the effects of phenolic extracts derived from Magnolia officinalis on the regulation of NAFLD. Specifically, we investigated the impact of Magnolol or Honokiol treatment on high-fat diet (HFD)-induced obese C57BL6/J male mice. Firstly, we monitored energy metabolism, dissected tissues, and analyzed tissue sections. Additionally, we conducted experiments on HepG2 and primary adipocytes to gain insights into the roles of Magnolol or Honokiol. To further understand the effects of these compounds on related signaling pathways and marker genes, we performed molecular docking, dual-luciferase assays, and interfered with target genes. Our findings revealed that Magnolol or Honokiol activate the peroxisome proliferator activated receptor alpha (PPARα) signaling pathway, leading to the alleviation of NAFLD. This activation promotes fatty acid oxidation, reduces lipogenesis, and enhances the expression and secretion of FGF21. Notably, Fibroblast growth factor 21 (FGF21), secreted by the liver, plays a crucial role in improving communication between the liver and adipocytes while also promoting the browning of adipose tissue. Additionally, Magnolol or Honokiol activate the peroxisome proliferator activated receptor gamma (PPARγ) signaling pathway, resulting in increased uncoupling protein 1 (UCP1) expression, heightened heat production in adipose tissue, and anti-obesity. Therefore, Magnolol or Honokiol alleviate NAFLD, promote adipose tissue browning and resist obesity through dual activation of PPARα/γ.

Exosomes derived from Baicalin-pretreated bone mesenchymal stem cells improve Th17/Treg imbalance after hepatic ischemia-reperfusion via FGF21 and the JAK2/STAT3 pathway.

Baicalin is an active compound extracted from Scutellaria baicalensis with antioxidant and anti-inflammatory properties. Bone mesenchymal stem cells (BMSCs)-derived exosomes have shown promise for the treatment of hepatic ischemia-reperfusion (I/R) injury. This study aims to investigate the role of Baicalin-pretreated BMSCs-derived exosomes in hepatic I/R injury and its mechanisms. BMSCs were pretreated with or without Baicalin, and their exosomes (Ba-Exo and Exo) were collected and characterized. These exosomes were administered to mice via tail vein injection. Treatment with Exo and Ba-Exo significantly suppressed the elevation of ALT and AST induced by hepatic injury. Additionally, both Exo and Ba-Exo treatments resulted in a reduction in the liver weight-to-body weight ratio. RT-PCR results revealed a significant downregulation of pro-inflammatory cytokines with Exo and Ba-Exo treatment. Both Exo and Ba-Exo treatment improved the Th17/Treg cell imbalance induced by I/R and reduced hepatic injury. Additionally, exosomes were cocultured with normal liver cells, and the expression of fibroblast growth factor 21 (FGF21) in liver cells was elevated through Ba-Exo treatment. After treatment, the JAK2/STAT3 pathway was inhibited, and FOXO1 expression was upregulated. Finally, recombinant FGF21 was injected into mouse tail veins to assess its effects. Recombinant FGF21 injection further inhibited the JAK2/STAT3 pathway, increased FOXO1 expression, and improved the Th17/Treg cell imbalance. In conclusion, this study confirms the protective effects of Exo and Ba-Exo against hepatic I/R injury. Ba-Exo mitigates hepatic I/R injury, achieved through inducing FGF21 expression in liver cells, inhibiting the JAK2/STAT3 pathway, and activating FOXO1 expression. Therefore, baicalin pretreatment emerges as a promising strategy to enhance the therapeutic capability of BMSCs-derived exosomes for hepatic I/R.

ATF4 expression in thermogenic adipocytes is required for cold-induced thermogenesis in mice via FGF21-independent mechanisms

In brown adipose tissue (BAT), short-term cold exposure induces the activating transcription factor 4 (ATF4), and its downstream target fibroblast growth factor 21 (FGF21). Induction of ATF4 in BAT in response to mitochondrial stress is required for thermoregulation, partially by increasing FGF21 expression. In the present study, we tested the hypothesis that Atf4 and Fgf21 induction in BAT are both required for BAT thermogenesis under physiological stress by generating mice selectively lacking either Atf4 (ATF4 BKO) or Fgf21 (FGF21 BKO) in UCP1-expressing adipocytes. After 3 days of cold exposure, core body temperature was significantly reduced in ad-libitum-fed ATF4 BKO mice, which correlated with Fgf21 downregulation in brown and beige adipocytes, and impaired browning of white adipose tissue. Conversely, despite having reduced browning, FGF21 BKO mice had preserved core body temperature after cold exposure. Mechanistically, ATF4, but not FGF21, regulates amino acid import and metabolism in response to cold, likely contributing to BAT thermogenic capacity under ad libitum-fed conditions. Importantly, under fasting conditions, both ATF4 and FGF21 were required for thermogenesis in cold-exposed mice. Thus, ATF4 regulates BAT thermogenesis under fed conditions likely in a FGF21-independent manner, in part via increased amino acid uptake and metabolism.

Treatment with dapagliflozin increases FGF-21 gene expression and reduces triglycerides content in myocardial tissue of genetically obese mice.

The association between obesity and some cardiovascular complications such as heart failure (HF) is well established, and drugs affecting adiposity are supposed to be promising treatments for these conditions. The sodium-glucose cotransporter-2 inhibitors (SGLT2i) are antidiabetic drugs showing benefits in patients with HF, despite the underlying mechanisms have not been completely understood yet. SGLT2i are supposed to promote systemic effects, such as triglycerides mobilization, through the enhancement of fibroblast growth factor-21 (FGF-21) activity. So, in this study, weevaluated the effects of dapagliflozin treatment on FGF-21 and related receptors (FGF-Rs) gene expression and on lipid content in myocardial tissue in an animal model of genetically induced obesity to unravel possible metabolic mechanisms accounting for the cardioprotection of SGLT2i. Six-week-old C57BL/6J wild-type mice and B6.V-LEP (ob/ob) mice were randomly assigned to the control or treatment group (14 animals/group). Treatment was based on the administration of dapagliflozin 0.15mg/kg/day for 4weeks. The gene expression of FGF-21 and related receptors (FGF-R1, FGF-R3, FGF-R4, and β-klotho co-receptor) was assessed at baseline and after treatment by real-time PCR. Similarly, cardiac triglycerides concentration was measured in the control group and treated animals. At baseline, FGF-21 mRNA expression in the heart did not differ between lean and obese ob/ob mice. Dapagliflozin administration significantly increased heart FGF-21 gene expression, but only in ob/ob mice (p < 0.005). Consistently, when measuring the amount of triglycerides in the cardiac tissue, SGLT2i treatment reduced the lipid content in obese ob/ob mice, while no significant effects were observed in treated lean animals (p < 0.001). The overall expression of the FGF-21 receptors was only minimally affected by dapagliflozin treatment both in obese ob/ob mice and in lean controls. Dapagliflozin administrationincreases FGF-21gene expression and reduces triglyceride content in myocardial tissue of ob/ob mice, while no significant effect was observed in lean controls. These results might help understand the cardiometabolic effects of SGLT2i inducing increased FGF-21 synthesis while reducing lipid content in cardiomyocytes as a possible expression of the switch to different energy substrates. This mechanism could represent a potential target of SGLT2i in obesity-related heart diseases.

Grape seed-derived procyanidin inhibits glyphosate-induced hepatocyte ferroptosis via enhancing crosstalk between Nrf2 and FGF12

BackgroundGlyphosate (GLY) exposure induces hepatocyte ferroptosis through overproduction of reactive oxygen species, regarded as an important contributor to liver damage. Grape seed-derived procyanidin (GSDP) has been reported to be an effective antioxidant, but whether and, if any, how GSDP can attenuate GLY-induced liver injury via inhibiting ferroptosis is unclear. PurposeThe current study aimed to investigate the hepato-protective effects and possible mechanisms of GSDP. MethodsGLY-induced liver damage mice model was established to explore the hepatoprotective roles of GSPE in vivo. Subsequently, bioinformatics methodology was used to predict the key pathways and factors related to the action targets of GSPE against hepatocyte ferroptosis. Finally, we explored the roles of nuclear factor E2 related factor 2 (Nrf2) and fibroblast growth factor 21 (FGF21) in blunting GLY-induced liver damage via suppressing ferroptosis in vitro. ResultsGSDP exerts hepato-protective effects in vivo and in vitro through reduced oxidative stress and inhibited ferroptosis, which was related to the activation of Nrf2. Bioinformatics analysis showed an interaction between Nrf2 and FGF21. Furthermore, Nrf2 inhibition reduced FGF21 expression in the mRNA and protein levels. Fgf21 knockdown suppressed Nrf2 expression level, but recombinant FGF21 protein increased Nrf2 expression and promoted Nrf2 translocation into nucleus, suggesting a crosstalk between Nrf2 and FGF21. Intriguingly, the decreased levels of Nrf2 and FGF21 compromised the protective roles of GSDP against GLY-induced hepatocyte ferroptosis. ConclusionThese findings suggest that GSDP attenuates GLY-caused hepatocyte ferroptosis via enhancing the interplay between Nrf2 and FGF21. Thus, GSDP may be a promising natural compound to antagonize ferroptosis-related damage.

Berberine protects mice against type 2 diabetes by promoting PPARγ-FGF21-GLUT2-regulated insulin sensitivity and glucose/lipid homeostasis

Type 2 diabetes (T2D) is a chronic, burdensome disease that is characterized by disordered insulin sensitivity and disturbed glucose/lipid homeostasis. Berberine (BBR) has multiple therapeutic actions on T2D, including regulation of glucose and lipid metabolism, improvement of insulin sensitivity and energy expenditure. Recently, the function of BBR on fibroblast growth factor 21 (FGF21) has been identified. However, if BBR ameliorates T2D through FGF21, the underlying mechanisms remain unknown. Herein, we used T2D wild type (WT) and FGF21 global knockout (FKO) mice [mouse T2D model: established by high-fat diet (HFD) feeding plus streptozotocin (STZ) injection], and hepatocyte-specific peroxisome proliferator activated receptor γ (PPARγ) deficient (PPARγHepKO) mice, and cultured human liver carcinoma cells line, HepG2 cells, to characterize the role of BBR in glucose/lipid metabolism and insulin sensitivity. We found that BBR activated FGF21 expression by up-regulating PPARγ expression at the cellular level. Meanwhile, BBR ameliorated glucosamine hydrochloride (Glcn)-induced insulin resistance and increased glucose transporter 2 (GLUT2) expression in a PPARγ/FGF21-dependent manner. In T2D mice, BBR up-regulated the expression of PPARγ, FGF21 and GLUT2 in the liver, and GLUT2 in the pancreas. BBR also reversed T2D-induced insulin resistance, liver lipid accumulation, and damage in liver and pancreas. However, FGF21 deficiency diminished these effects of BBR on diabetic mice. Altogether, our study demonstrates that the therapeutic effects of BBR on T2D were partly accomplished by activating PPARγ-FGF21-GLUT2 signaling pathway. The discovery of this new pathway provides a deeper understanding of the mechanism of BBR for T2D treatment.

244 Fgf-21 Myokine Expression By Cultured Bovine Satellite Cells from 3- and 11-Month-Old Steers

Abstract 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.

Fibroblast growth factor 21 alleviates unilateral ureteral obstruction-induced renal fibrosis by inhibiting Wnt/β-catenin signaling pathway

Fibroblast growth factor 21 (FGF21) is a key regulator of energy metabolism. Recent studies suggested that serum FGF21 levels increase with declining renal function. However, the link between FGF21 and kidney diseases and the direct effect of FGF21 in renal fibrosis remains unclear. In this study, FGF21 was upregulated in unilateral ureteral obstruction (UUO)-induced renal fibrosis and cellular fibrosis induced by transforming growth factor-β, and renal expression of FGF21 was positively correlated with fibrosis markers. Additionally, FGF21 was regulated by Wnt/β-catenin signaling pathway. The knockdown and overexpression of FGF21 in mouse tubular epithelial cells demonstrated that FGF21 alleviates renal fibrosis by inhibiting the Wnt/β-catenin signaling pathway. To investigate the effect of FGF21 on renal fibrosis in vivo, we established an overexpression model by injecting the plasmid in mice and found that FGF21 overexpression relieved UUO-induced renal fibrosis and renal inflammatory response. Taken together, FGF21 is upregulated with the activation of Wnt/β-catenin signaling pathway and alleviates renal fibrosis by inhibiting the activation of Wnt/β-catenin signaling pathway in a negative feedback mode. These results provide a new understanding for the source of elevated serum FGF21 in patients with chronic kidney disease and prove that FGF21 is a direct inhibitor of the progression of renal fibrosis, thus providing novel therapeutic intervention insights for renal fibrosis.

Fibroblast Growth Factor 21 Relieves Lipopolysaccharide-Induced Acute Lung Injury by Suppressing JAK2/STAT3 Signaling Pathway

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a life‐threatening disease without an effective drug at present. Fibroblast growth factor 21 (FGF21) was reported to be protective against inflammation in metabolic disease in recent studies. However, the role of FGF21 in ALI has been rarely investigated. In this study, it was found that the expression of FGF21 was markedly increased in lung tissue under lipopolysaccharide (LPS) stimulation in vivo, whereas it was decreased in lung epithelial cells under LPS stimulation in vitro. Therefore, our research aimed to elucidate the potential role of FGF21 in LPS-induced ALI and to detect possible underlying mechanisms. The results revealed that the deficiency of FGF21 aggravated pathological damage, inflammatory infiltration, and pulmonary function in LPS-induced ALI, while exogenous administration of FGF21 improved these manifestations. Moreover, through RNA sequencing and enrichment analysis, it was unveiled that FGF21 might play a protective role in LPS-induced ALI via JAK2/STAT3 signaling pathway. The therapeutic effect of FGF21 was weakened after additional usage of JAK2 activator in vivo. Further investigation revealed that FGF21 significantly inhibited STAT3 phosphorylation and impaired the nuclear translocation of STAT3 in vitro. In addition, the aggravation of inflammation caused by silencing FGF21 can be alleviated by JAK2 inhibitor in vitro. Collectively, these findings unveil a potent protective effect of FGF21 against LPS-induced ALI by inhibiting the JAK2/STAT3 pathway, implying that FGF21 might be a novel and effective therapy for ALI.

Effective fraction of Gualou-Xiebai-Banxia decoction inhibits the apoptosis of myocardial cells induced by ox-LDL via FGF21/FGFR1/βKlotho-FRS2α signal pathway

Ethnopharmacological relevanceThe Gualou-Xiebai-Banxia decoction (GXBD), a classical traditional Chinese medicine (TCM) formula, has beneficial effects in turbid phlegm obstruction syndrome, a type of coronary heart disease (CHD). However, the underlying mechanism and effective constituents of GXBD remain elusive. Our previous studies have shown that the effective constituents of GXBD may be enriched in the n-butanol fraction (GXB-N) and water fraction (GXB-W), the targets of which remain unknown. Aim of the studyTo investigate whether GXB-N and GXB-W protect myocardial cells (MCs) via fibroblast growth factor 21 (FGF21) signaling and, if so, to elucidate the underlying mechanisms. Furthermore, to investigate the targets of GXB-N and GXB-W as potential therapeutic targets for cardiovascular disease (CVD). Materials and methodsCell viability and apoptosis were assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays, respectively. The content of FGF21 in the medium was measured using enzyme-linked immunosorbent assay (ELISA). Protein expression was detected using immunofluorescence and western blotting. ResultsApoptosis increased markedly in MCs exposed to oxidized low density lipoprotein (ox-LDL) 100 μg/mL, with increased expression of FGF21, FGFR1 and βKlotho, phosphorylation of fibroblast receptor substrate 2α (FRS2α) was suppressed. Following incubation with GXB-N and GXB-W 200 μg/mL, the expression of FGF21, FGFR1, and βKlotho and the phosphorylation of FRS2α were increased. ConclusionOx-LDL may inhibit the phosphorylation of FRS2α, inducing considerable FGF21 resistance and resulting in MC apoptosis. GXB-N and GXB-W restored and enhanced FGF21 sensitivity in MCs, consequently rescuing cells from ox-LDL-induced apoptosis. The FGF21-FRS2α signal pathway may be part action targets of these two effective fractions of GXBD.

FGF21 promotes myocardial angiogenesis and mediates the cardioprotective effects of exercise in myocardial infarction mice.

The mechanism by which aerobic exercise promotes cardiac function after myocardial infarction (MI) is still not fully understand. In this study, we investigated the role of fibroblast growth factor 21 (FGF21) in exercise protecting the cardiac function of MI mice. In vivo, MI was induced by left anterior descending coronary artery ligation in wild-type and fgf21 knockout mice on the C57BL/6 background. One week after MI, the mice underwent aerobic exercise for 4 wk. In vitro, human umbilical vein endothelial cells (HUVECs) were treated with H2O2, recombinant human FGF21 (rhFGF21), fibroblast growth factor receptor 1 (FGFR1) inhibitor (PD166866), and phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002) to explore the potential mechanisms. Scratch wound healing and tubule formation analysis were used to detect the migration and tubule formation ability of HUVECs. Our results showed that aerobic exercise significantly promoted angiogenesis and cardiac function through enhancing the expression of FGF21 and activating FGFR1/PI3K/AKT/VEGF pathway. But such changes in cardiac from aerobic exercise were attenuated by fgf21 knockout mice. 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) enhanced angiogenesis and cell migration through FGF21/FGFR1/PI3K/AKT/VEGF signaling pathway. Under the intervention of H2O2, rhFGF21 also played the role of promoting angiogenesis and cell migration through the same mechanism. In conclusion, our results showed that FGF21 promoted the aerobic exercise-induced angiogenesis and improved cardiac function via FGFR1/PI3K/AKT/VEGF signal in MI mice.NEW & NOTEWORTHY FGF21 activated FGFR1/PI3K/AKT/VEGF signaling pathway mediated angiogenesis in MI mice. FGF21 deficiency attenuated aerobic exercise-induced cardiac angiogenesis in MI mice. FGF21/FGFR1/PI3K/AKT/VEGF signal played an important role in aerobic exercise to promote myocardial angiogenesis and improved cardiac function.

The potential effect of metformin on fibroblast growth factor 21 in type 2 diabetes mellitus (T2DM).

Fibroblast growth factor 21 (FGF21) is a peptide hormone mainly synthesized and released from the liver. FGF21 acts on FGF21 receptors(FGFRs) and β-Klotho, which is a transmembrane co-receptor. In type 2 diabetes mellitus (T2DM), inflammatory disorders stimulate the release of FGF21 to overcome insulin resistance (IR). FGF21 improves insulin sensitivity and glucose homeostasis. Metformin which is used in the management of T2DM may increase FGF21 expression. Accordingly, the objective of this review was to clarify the metformin effect on FGF21 in T2DM. FGF21 level and expression of FGF2Rs are dysregulated in T2DM due to the development of FGF21 resistance. Metformin stimulates the hepatic expression of FGF21/FGF2Rs by different signaling pathways. Besides, metformin improves the expression of β-Klotho which improves FGF21 sensitivity. In conclusion, metformin advances FGF21 signaling and decreases FGF21 resistance in T2DM, and this might be an innovative mechanism for metformin in the enhancement of glucose homeostasis and metabolic disorders in T2DM patients.

CCE and EODF as two distinct non-shivering thermogenesis models inducing weight loss.

Increasing energy expenditure and reducing energy intake are considered two classical methods to induce weight loss. Weight loss through physical methods instead of drugs has been a popular research topic nowadays, but how these methods function in adipose and cause weight loss in body remains unclear. In this study, we set up chronic cold exposure (CCE) and every-other-day fasting (EODF) as two distinct models in long-term treatment to induce weight loss, recording their own characteristics in changes of body temperature and metabolism. We investigated the different types of non-shivering thermogenesis induced by CCE and EODF in white and brown adipose tissue through sympathetic nervous system (SNS), creatine-driven pathway, and fibroblast growth factor 21 (FGF21)-adiponectin axis. CCE and EODF could reduce body weight, lipid composition, increase insulin sensitivity, promote the browning of white fat, and increase the expression of endogenous FGF21 in adipose tissue. CCE stimulated the SNS and increased the thermogenic function of brown fat, and EODF increased the activity of protein kinase in white fat. In this study, we further explained the thermogenic mechanism function in adipose and metabolic benefits of the stable phenotype through physical treatments used for weight loss, providing more details for the literature on weight loss models. The influence on metabolism, non-shivering thermogenesis, endogenous FGF21, and ADPN changes in the long-term treatment of distinct methods (increasing energy expenditure and decreasing energy intake) to induce weight loss.

Investigation of FGF21 mRNA levels and relative mitochondrial DNA copy number levels and their relation in nonalcoholic fatty liver disease: a case-control study.

Background: Although the exact mechanisms of nonalcoholic fatty liver disease (NAFLD) are not fully understood, numerous pieces of evidence show that the variations in mitochondrial DNA (mtDNA) level and hepatic Fibroblast growth factor 21 (FGF21) expression may be related to NAFLD susceptibility. Objectives: The main objective of this study was to determine relative levels of mtDNA copy number and hepatic FGF21 expression in a cohort of Iranian NAFLD patients and evaluate the possible relationship. Methods: This study included 27 NAFLD patients (10 with nonalcoholic fatty liver (NAFL) and 17 with non-alcoholic steatohepatitis (NASH)) and ten healthy subjects. Total RNA and genomic DNA were extracted from liver tissue samples, and then mtDNA copy number and FGF21 expression levels were assessed by quantitative real-time PCR. Results: The relative level of hepatic mtDNA copy number was 3.9-fold higher in patients than in controls (p < 0.0001). NAFLD patients showed a 2.9-fold increase in hepatic FGF21 expression compared to controls (p < 0.013). Results showed that hepatic FGF21 expression was positively correlated with BMI, serum ALT, and AST levels (p < 0.05). The level of mitochondrial copy number and hepatic FGF21 expression was not significantly associated with stages of change in hepatic steatosis. Finally, there was a significant correlation between FGF21 expression and mitochondrial copy number in NAFLD patients (p = 0.027). Conclusion: Our findings suggest a considerable rise of hepatic FGF21 mRNA levels and mtDNA-CN and show a positive correlation between them in the liver tissue of NAFLD patients.