Fibroblast Growth Factor 21 Production Research Articles

Characterization of FGF21 Sites of Production and Signaling in Mice.

Fibroblast growth factor (FGF) 21 is an endocrine hormone that signals to multiple tissues to regulate metabolism. FGF21 and another endocrine FGF, FGF15/19, signal to target tissues by binding to the co-receptor β-klotho (KLB), which then facilitates the interaction of these different FGFs with their preferred FGF receptor. KLB is expressed in multiple metabolic tissues, but the specific cell types and spatial distribution of these cells are not known. Furthermore, while circulating FGF21 is primarily produced by the liver, recent publications have indicated that brain-derived FGF21 impacts memory and learning. Here we use reporter mice to comprehensively assess KLB and FGF21 expression throughout the body. These data provide an important resource for guiding future studies to identify important peripheral and central targets of FGFs and to determine the significance of nonhepatic FGF21 production.

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.

Fibroblast Growth Factor 21: A Fascinating Perspective on the Regulation of Muscle Metabolism.

Fibroblast growth factor 21 (FGF21) plays a vital role in normal eukaryotic organism development and homeostatic metabolism under the influence of internal and external factors such as endogenous hormone changes and exogenous stimuli. Over the last few decades, comprehensive studies have revealed the key role of FGF21 in regulating many fundamental metabolic pathways, including the muscle stress response, insulin signaling transmission, and muscle development. By coordinating these metabolic pathways, FGF21 is thought to contribute to acclimating to a stressful environment and the subsequent recovery of cell and tissue homeostasis. With the emphasis on FGF21, we extensively reviewed the research findings on the production and regulation of FGF21 and its role in muscle metabolism. We also emphasize how the FGF21 metabolic networks mediate mitochondrial dysfunction, glycogen consumption, and myogenic development and investigate prospective directions for the functional exploitation of FGF21 and its downstream effectors, such as the mammalian target of rapamycin (mTOR).

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 < 0.0001). The media from the BSC of the 11-month-old steers had greater (P < 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 < 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 in Chronic Hepatitis C: A Potential Non-Invasive Biomarker of Liver Status upon Viral Eradication.

Fibroblast growth factor 21 (FGF-21), previously recognized as a marker of liver damage and a potential drug target in non-alcoholic fatty liver disease (NAFLD), has unclear implications in hepatitis C virus (HCV) infections. This study aimed to investigate the relationship between FGF-21 levels and liver health in patients with HCV undergoing direct-acting antiviral (DAA) treatment. Forty-five patients were assessed for liver stiffness, blood chemistry, and other relevant metrics before and after achieving sustained viral response (SVR), defined as the absence of detectable HCV-RNA after 24 weeks of treatment. Post-treatment, all patients showed a decrease in liver stiffness and improved liver enzyme levels (AST and ALT), alongside an increase in FGF-21 levels. Interestingly, the increase in FGF-21 correlated negatively with liver stiffness but showed no correlation with hepatic steatosis. The observed elevation in FGF-21 levels at SVR following DAA therapy for chronic HCV infection can be attributed to the restoration of hepatic function, including its synthetic capabilities. Specifically, the mitigation of liver fibrosis post-HCV eradication is expected to lead to improvements in liver function, such as enhanced albumin and FGF-21 production. This improvement in synthetic function likely drives the increase in FGF-21 levels, rather than changes in liver fat content. We suggest a potential role of FGF-21 as a marker of fibrosis and hepatic cytotoxicity and as a drug target beyond NAFLD, to be confirmed by additional studies.

Abstract 638: EPB-53 prevents NASH-HCC transition via regulation of SPHK1-S1P-HIPPO signaling and immune modulation in a murine model

Abstract Background: Non-alcoholic fatty liver disease (NAFLD) encompasses a broad spectrum of disorders, ranging from non-progressive bland steatosis to non-alcoholic hepatitis (NASH), cirrhosis, and malignant transformation into hepatocellular carcinoma (HCC). Fibroblast growth factor 21 (FGF21) exerts a key role in lipid homeostasis and play a promising therapeutic candidate for the treatment of obesity, diabetes, and NASH. Small molecules like EPB-53 that are activators of heme-regulated inhibitor (HRI) of eukaryotic initiation factor 2α (eIF2α) kinase have been synthesized to induce FGF21. Previous study has shown that oral administration of EPB-53 alleviates NASH through increased FGF21 to prevent hepatic steatosis. However, it is unknown whether EPB-53 can prevent NASH-HCC transition. Aim: To investigate the effect of EPB-53 on NASH-HCC transition and the therapeutic mechanism, focusing on the lipid metabolic reprogramming and tumor immune microenvironment (TIM). Methods: NASH-HCC transition model was established in two-week-old male FGF21 knockout (KO) mice and wild type controls (C57BL/6J mice) by diethylnitrosamine (DEN) administration at 40 mg/kg body weight (i.p.). Four weeks after DEN administration, the mice were fed with western-style high fat diet (WSHFD, 60% kcal% fat and 19% kcal% fructose) for 3 months, and gavaged daily with either vehicle, 2% w/v, (2-hydroxypropyl)-β-cyclodextrin or EPB-53 (300 mg/kg/day) in vehicle for 4 weeks before sacrifice. The tumor incidence, lipid metabolism, and carcinogenesis signaling pathways were determined. Mass cytometry (CyTOF) analysis was performed to detect the cell subpopulations in the NASH microenvironment and NASH-HCC TIM. Results: Severe NASH with tumor cell detection, aberrant lipid components and HIPPO-YAP signaling were found in liver tissues of FGF21-KO mice compared to the WT controls. The upregulated sphingosine Kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) in liver subsequently induced YAP dephosphorylation and nuclear localization. EPB-53 treatment prevents NASH-HCC transition evident as decreased HCC incidence in WT mice but not in FGFKO mice. Continuously increased FGF21 production in WT mice contributes to down-regulation of SPHK1-S1P-HIPPO-YAP signaling. Interestingly, EPB-53 treatment can alleviate the compromised function of macrophages/Kupffer cells which render a TIM in the NASH-HCC mice. Conclusion: 1) Lack of FGF21 played a key role in lipid metabolic disorder and SPHK1-S1P-HIPPO signaling to promote NASH-HCC transition; 2) Lack of FGF21 rendered a TIM in NASH liver contributing to the NASH-HCC transition; 3) EPB-53 treatment can not only alleviate NASH, but also prevent NASH-HCC transition via lipid metabolic reprogramming, down-regulation of the SPHK1-S1P-HIPPO axis, and modulation of TIM. Citation Format: Min Tan, Eugenia Pujol, Santiago Vazquez, Jingwen Zhang, Jun Yan, Robert C. Martin, Manuel Vazquez-Carrera, Yan Li. EPB-53 prevents NASH-HCC transition via regulation of SPHK1-S1P-HIPPO signaling and immune modulation in a murine model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 638.

Fibroblast growth factor 21 is expressed and secreted from skeletal muscle following electrical stimulation via extracellular ATP activation of the PI3K/Akt/mTOR signaling pathway.

Fibroblast growth factor 21 (FGF21) is a hormone involved in the regulation of lipid, glucose, and energy metabolism. Although it is released mainly from the liver, in recent years it has been shown that it is a "myokine", synthesized in skeletal muscles after exercise and stress conditions through an Akt-dependent pathway and secreted for mediating autocrine and endocrine roles. To date, the molecular mechanism for the pathophysiological regulation of FGF21 production in skeletal muscle is not totally understood. We have previously demonstrated that muscle membrane depolarization controls gene expression through extracellular ATP (eATP) signaling, by a mechanism defined as "Excitation-Transcription coupling". eATP signaling regulates the expression and secretion of interleukin 6, a well-defined myokine, and activates the Akt/mTOR signaling pathway. This work aimed to study the effect of electrical stimulation in the regulation of both production and secretion of skeletal muscle FGF21, through eATP signaling and PI3K/Akt pathway. Our results show that electrical stimulation increases both mRNA and protein (intracellular and secreted) levels of FGF21, dependent on an extracellular ATP signaling mechanism in skeletal muscle. Using pharmacological inhibitors, we demonstrated that FGF21 production and secretion from muscle requires the activation of the P2YR/PI3K/Akt/mTOR signaling pathway. These results confirm skeletal muscle as a source of FGF21 in physiological conditions and unveil a new molecular mechanism for regulating FGF21 production in this tissue. Our results will allow to identify new molecular targets to understand the regulation of FGF21 both in physiological and pathological conditions, such as exercise, aging, insulin resistance, and Duchenne muscular dystrophy, all characterized by an alteration in both FGF21 levels and ATP signaling components. These data reinforce that eATP signaling is a relevant mechanism for myokine expression in skeletal muscle.

Wogonin, a Compound in Scutellaria baicalensis, Activates ATF4-FGF21 Signaling in Mouse Hepatocyte AML12 Cells.

Fibroblast growth factor 21 (FGF21), which is mainly synthesized and secreted by the liver, plays a crucial role in systemic glucose and lipid metabolism, ameliorating metabolic diseases. In this study, we screened the WAKANYAKU library derived from medicinal herbs to identify compounds that can activate Fgf21 expression in mouse hepatocyte AML12 cells. We identified Scutellaria baicalensis root extract and one of its components, wogonin, as an activator of Fgf21 expression. Wogonin also enhanced the expression of activating transcription factor 4 (ATF4) by a mechanism other than ER stress. Knockdown of ATF4 by siRNA suppressed wogonin-induced Fgf21 expression, highlighting its essential role in wogonin’s mode of action. Thus, our results indicate that wogonin would be a strong candidate for a therapeutic to improve metabolic diseases by enhancing hepatic FGF21 production.

Central FGF21 production regulates memory but not peripheral metabolism.

SUMMARYFibroblast growth factor 21 (FGF21) is a liver-derived endocrine hormone that functions to regulate energy homeostasis and macronutrient intake. Recently, FGF21 was reported to be produced and secreted from hypothalamic tanycytes, to regulate peripheral lipid metabolism; however, rigorous investigation of FGF21 expression in the brain has yet to be accomplished. Using a mouse model that drives CRE recombinase in FGF21-expressing cells, we demonstrate that FGF21 is not expressed in the hypothalamus, but instead is produced from the retrosplenial cortex (RSC), an essential brain region for spatial learning and memory. Furthermore, we find that central FGF21 produced in the RSC enhances spatial memory but does not regulate energy homeostasis or sugar intake. Finally, our data demonstrate that administration of FGF21 prolongs the duration of long-term potentiation in the hippocampus and enhances activation of hippocampal neurons. Thus, endogenous and pharmacological FGF21 appear to function in the hippocampus to enhance spatial memory.

Fibroblast growth factor 21 as a new tool in the multicomponent assessment of cardiovascular diseases

Currently, the search and study of new biological markers that can assist in the early diagnosis of cardiovascular diseases, serving as a laboratory tool for assessing the efficiency of ongoing therapy and being a prognostic criterion of possible clinical outcomes and a significant indicator in risk stratification, remain relevant. Two decades have passed since fibroblast growth factor 21 (FGF21), the 21st member of the FGF family, was identified and cloned. FGF21 is a secreted protein that acts as a metabolic regulator and participates in glucose homeostasis, ketogenesis, and regulation of insulin sensitivity. FGF21 expression is controlled by PPAR alpha receptor, which activates peroxisome proliferation. The liver is the main site of FGF21 production. Extrahepatic tissues such as white adipose tissue, brown adipose tissue, and skeletal muscle also express FGF21. Human FGF21 contains 209 amino acids, whereas the mouse counterpart has 210. Mouse and human FGF21 have 75% homology. Endocrine actions of FGF21 include enhancing glucose uptake by adipocytes of white adipose tissue via a unidirectional glucose transporter protein and activating the thermogenic function of brown adipose tissue. Furthermore, FGF21 has autocrine/paracrine effects, such as the induction of hepatic ketogenesis. FGF21 affects target cells with the participation of FGFR1 and FGFR4 receptors and beta-Klotho, a single-pass transmembrane protein that functions as an obligate cofactor of FGF21 signaling. Animal studies have clearly demonstrated that FGF21 acts directly on cardiac tissue, preventing the development of cardiac hypertrophy and reducing post-infarction damage and diabetic cardiomyopathy. Accumulating data emphasize the value of FGF21 as a new biological marker for diagnosis and prognosis assessment in patients with cardiac issues. Moreover, the role of FGF21 in heart diseases is very interesting because of its cardioprotective effects. Future large-scale prospective studies are necessary to confirm of the diagnostic, predictive, and possibly therapeutic role of this marker.

ATGL-dependent white adipose tissue lipolysis controls hepatocyte PPARα activity.

In hepatocytes, peroxisome proliferator-activated receptor α (PPARα) orchestrates a genomic and metabolic response required for homeostasis during fasting. This includes the biosynthesis of ketone bodies and of fibroblast growth factor 21 (FGF21). Here we show that in the absence of adipose triglyceride lipase (ATGL) in adipocytes, ketone body and FGF21 production is impaired upon fasting. Liver gene expression analysis highlights a set of fasting-induced genes sensitive to both ATGL deletion in adipocytes and PPARα deletion in hepatocytes. Adipose tissue lipolysis induced by activation of the β3-adrenergic receptor also triggers such PPARα-dependent responses not only in the liver but also in brown adipose tissue (BAT). Intact PPARα activity in hepatocytes is required for the cross-talk between adipose tissues and the liver during fat mobilization.

Hepatocyte-Secreted Autotaxin Exacerbates Nonalcoholic Fatty Liver Disease Through Autocrine Inhibition of the PPARα/FGF21 Axis.

Background & AimsThe prevalence of nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions globally as a result of the rapid increase in obesity. However, there is no Food and Drug Administration–approved pharmacotherapy available for NAFLD. This study investigated the role of autotaxin, a secreted enzyme that hydrolyzes lysophosphatidylcholine to produce lysophosphatidic acid (LPA), in the pathogenesis of NAFLD and to explore whether genetic or pharmacologic interventions targeting autotaxin ameliorate NAFLD.MethodsThe clinical association of autotaxin with the severity of NAFLD was analyzed in 125 liver biopsy-proven NAFLD patients. C57BL/6N mice or fibroblast growth factor 21 (FGF21)-null mice were fed a high-fat diet or a choline-deficient diet to investigate the role of the autotaxin–FGF21 axis in NAFLD development by hepatic knockdown and antibody neutralization. Huh7 cells were used to investigate the autocrine effects of autotaxin.ResultsSerum autotaxin levels were associated positively with histologic scores and NAFLD severity. Hepatocytes, but not adipocytes, were the major contributor to increased circulating autotaxin in both patients and mouse models with NAFLD. In mice, knocking-down hepatic autotaxin or treatment with a neutralizing antibody against autotaxin significantly reduced high-fat diet–induced NAFLD and high fat– and choline-deficient diet–induced nonalcoholic steatohepatitis and fibrosis, accompanied by a marked increase of serum FGF21. Mechanistically, autotaxin inhibited the transcriptional activity of peroxisome proliferator-activated receptor α through LPA-induced activation of extracellular signal-regulated kinas, thereby leading to suppression of hepatic FGF21 production. The therapeutic benefit of anti-autotaxin neutralizing antibody against NAFLD was abrogated in FGF21-null mice.ConclusionsLiver-secreted autotaxin acts in an autocrine manner to exacerbate NAFLD through LPA-induced suppression of the peroxisome proliferator-activated receptor α–FGF21 axis and is a promising therapeutic target for NAFLD.

Acute sleep loss alters circulating fibroblast growth factor 21 levels in humans: A randomised crossover trial.

The hormone fibroblast growth factor 21 (FGF21) modulates tissue metabolism and circulates at higher levels in metabolic conditions associated with chronic sleep-wake disruption, such as type 2 diabetes and obesity. In the present study, we investigated whether acute sleep loss impacts circulating levels of FGF21 and tissue-specific production, and response pathways linked to FGF21. A total of 15 healthy normal-weight young men participated in a randomised crossover study with two conditions, sleep loss versus an 8.5-hr sleep window. The evening before each intervention, fasting blood was collected. Fasting, post-intervention morning skeletal muscle and adipose tissue samples underwent quantitative polymerase chain reaction and DNA methylation analyses, and serum FGF21 levels were measured before and after an oral glucose tolerance test. Serum levels of FGF21 were higher after sleep loss compared with sleep, both under fasting conditions and following glucose intake (~27%-30%, p=0.023). Fasting circulating levels of fibroblast activation protein, a protein which can degrade circulating FGF21, were not altered by sleep loss, whereas DNA methylation in the FGF21 promoter region increased only in adipose tissue. However, even though specifically the muscle exhibited transcriptional changes indicating adverse alterations to redox and metabolic homeostasis, no tissue-based changes were observed in expression of FGF21, its receptors, or selected signalling targets, in response to sleep loss. In summary, we found that acute sleep loss resulted in increased circulating levels of FGF21 in healthy young men, which may occur independent of a tissue-based stress response in metabolic peripheral tissues. Further studies may decipher whether changes in FGF21 signalling after sleep loss modulate metabolic outcomes associated with sleep or circadian disruption.

Transmembrane G protein-coupled receptor 5 signaling stimulates fibroblast growth factor 21 expression concomitant with up-regulation of the transcription factor nuclear receptor Nr4a1

Fibroblast growth factor 21 (FGF21) acts as an endocrine factor, playing important roles in the regulation of energy homeostasis, glucose and lipid metabolism. It is induced by diverse metabolic and cellular stresses, such as starvation and cold challenge, which in turn facilitate adaptation to the stress environment. The pharmacological action of FGF21 has received much attention, because the administration of FGF21 or its analogs has been shown to have an anti-obesity effect in rodent models. In the present study, we found that 3-O-acetyloleanolic acid, an active constituent isolated from the fruits of Forsythia suspensa, stimulated FGF21 production concomitant with the up-regulation of a transcription factor, nuclear receptor Nr4a1, in C2C12 myotubes. Additionally, significant increases in mFgf21 promoter activity were observed in C2C12 cells overexpressing TGR5 receptor in response to 3-O-acetyloleanolic acid treatment. Treatment with the p38 MAPK inhibitor SB203580 was effective at suppressing these stimulatory effects of 3-O-acetyloleanolic acid. Pretreatment with SB203580 also significantly repressed FGF21 mRNA abundance and FGF21 secretion in C2C12 myotubes after 3-O-acetyloleanolic acid stimulation, suggesting that p38 activation is required for the induction of FGF21 by ligand-activated TGR5 in C2C12 myotubes. These findings collectively indicated that TGR5 receptor signaling drives FGF21 expression via p38 activation, at least partly, by mediating Nr4a1 expression. Thus, the novel biological function of 3-O-acetyloleanolic acid as an agent having anti-obesity effects is likely to be mediated through the activation of TGR5 receptors.

Strong correlations between serum fibroblast growth factor 21 level and lipid parameters in patients with autoimmune thyroiditis

Background and Aims: Fibroblast growth factor 21 (FGF21) is a hormonal regulator of lipid and glucose metabolism exerting protection against atherosclerosis by multiple actions on the blood vessels, liver, and adipose tissues. Enhanced FGF21 production in diabetes and obesity reduces the level of LDL-C and triglycerides by suppression of hepatic SREBP-2. Hypothyroidism has also been shown to have unfavorable effects on atherogenesis and dyslipidemia. To date, the association of lipid parameters and FGF21 levels in autoimmune thyroiditis has not been studied.

Whey protein isolate inhibits hepatic FGF21 production, which precedes weight gain, hyperinsulinemia and hyperglycemia in mice fed a high-fat diet

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.

Glucosamine regulation of fibroblast growth factor 21 expression in liver and adipose tissues

Obesity is associated with metabolic disorders. Fibroblast growth factor 21 (FGF21) has been recognized as important in metabolism. Glucosamine (GLN) has been demonstrated to perform diverse beneficial functions. This study aimed to reveal whether and how GLN would modulate FGF21 production in relation to metabolism. With in vivo model of normal diet (ND) and high-fat diet (HFD) mice receiving GLN injection and in vitro model of mouse AML12 liver cells and differentiated 3T3L1 adipocytes challenged with GLN, GLN appeared to improve the glucose metabolism in HFD and ND mice and to elevate FGF21 protein expression in HFD liver and to increase both FGF21 protein and mRNA levels in WAT from HFD and ND mice and it also upregulated FGF21 expression in both AML12 and differentiated 3T3L1 cells. By using inhibitors against various signaling pathways, p38, Akt, NF-κB, and PKA appeared potentially involved in GLN-mediated FGF21 production in AML12 cells; GLN was able to mediate activation of NF-κB, p38 or PKA/CREB signaling. Our accumulated findings suggest that GLN may potentially improve the metabolic performance by inducing FGF21 production in liver and adipose tissues and such induction in liver cells may act in part due to GLN induction of the NF-κB, p38 and PKA pathways.

Propofol Improved Glucose Tolerance Associated with Increased FGF-21 and GLP-1 Production in Male Sprague-Dawley Rats.

Anesthetics, particularly volatile anesthetics, have been shown to impair glucose metabolism and cause hyperglycemia, closely linking them with mortality and morbidity as related to surgery. Beyond being an anesthetic used for general anesthesia and sedation, intravenous hypnotic propofol displays an effect on glucose metabolism. To extend the scope of propofol studies, its effects on glucose metabolism were evaluated in male Sprague-Dawley rats of various ages. Unlike chloral hydrate and isoflurane, propofol had little effect on basal glucose levels in rats at 2 months of age, although it did reduce chloral hydrate- and isoflurane-induced hyperglycemia. Propofol reduced postload glucose levels after either intraperitoneal or oral administration of glucose in both 7- and 12-month-old rats, but not those at 2 months of age. These improved effects regarding propofol on glucose metabolism were accompanied by an increase in insulin, fibroblast growth factor-21 (FGF-21), and glucagon-like peptide-1 (GLP-1) secretion. Additionally, an increase in hepatic FGF-21 expression, GLP-1 signaling, and FGF-21 signaling, along with a decrease in endoplasmic reticulum (ER) stress, were noted in propofol-treated rats at 7 months of age. Current findings imply that propofol may turn into insulin-sensitizing molecules during situations of existing insulin resistance, which involve FGF-21, GLP-1, and ER stress.

FGF21 Signals to Glutamatergic Neurons in the Ventromedial Hypothalamus to Suppress Carbohydrate Intake

Fibroblast growth factor 21 (FGF21) is an endocrine hormone produced by the liver that regulates nutrient and metabolic homeostasis. FGF21 production is increased in response to macronutrient imbalance and signals to the brain to suppress sugar intake and sweet-taste preference. However, the central targets mediating these effects have been unclear. Here, we identify FGF21 target cells in the hypothalamus and reveal that FGF21 signaling to glutamatergic neurons is both necessary and sufficient to mediate FGF21-induced sugar suppression and sweet-taste preference. Moreover, we show that FGF21 acts directly in the ventromedial hypothalamus (VMH) to specifically regulate sucrose intake, but not non-nutritive sweet-taste preference, body weight, or energy expenditure. Finally, our data demonstrate that FGF21 affects neuronal activity by increasing activation and excitability of neurons in the VMH. Thus, FGF21 signaling to glutamatergic neurons in the VMH is an important component of the neurocircuitry that functions to regulate sucrose intake.

Fibroblast growth factor 21 (FGF21) in children and adolescents with chronic kidney disease.

Fibroblast growth factor 21 (FGF21) is one of the members of endocrine arm of FGF family. Its actions as a glucose and lipids metabolism regulator are widely known. Although the mechanism of FGF21 action in kidneys is still under investigation, FGF21 was considered as a marker of early kidney function decline. While many researchers focused on adult subjects in this matter, there are no data regarding children. Therefore, we have investigated the relationship between plasma or urine FGF21 levels and kidney function in a group of 42 pediatric patients with chronic kidney disease (CKD). Anthropometrical parameters and blood pressure were taken, routine biochemical tests were performed. The concentration of FGF21 in serum and urine was determined by enzyme immunoassay. The results revealed significantly higher serum FGF21 concentration among children from CKD group. However, serum FGF21 level was not related to gender, proteinuria, eGFR or renal replacement therapy. Urine FGF21 concentration correlated negatively with albuminuria and positively with eGFR. Documented negative correlation of FGF21 fractional excretion and eGFR is not enough to support the role of FGF21 as a biomarker for predicting kidney disease progression in children and adolescents. Other mechanisms including local kidney FGF21 production or enhanced excretion due to higher extrarenal production may result in higher urine FGF21 concentrations.