Fibroblast Growth Factor 21 Expression Research Articles

Fibroblast Growth Factor 21 (FGF21) Protects against High Fat Diet Induced Inflammation and Islet Hyperplasia in Pancreas.

Fibroblast growth factor 21 (FGF21) is an important endocrine metabolic regulator expressed in multiple tissues including liver and adipose tissue. Although highest levels of expression are in pancreas, little is known about the function of FGF21 in this tissue. In order to understand the physiology of FGF21 in the pancreas, we analyzed its expression and regulation in both acinar and islet tissues. We found that acinar tissue express 20-fold higher levels than that observed in islets. We also observed that pancreatic FGF21 is nutritionally regulated; a marked reduction in FGF21 expression was noted with fasting while obesity is associated with 3–4 fold higher expression. Acinar and islet cells are targets of FGF21, which when systemically administered, leads to phosphorylation of the downstream target ERK 1/2 in about half of acinar cells and a small subset of islet cells. Chronic, systemic FGF21 infusion down-regulates its own expression in the pancreas. Mice lacking FGF21 develop significant islet hyperplasia and periductal lymphocytic inflammation when fed with a high fat obesogenic diet. Inflammatory infiltrates consist of TCRb+ Thy1+ T lymphocytes with increased levels of Foxp3+ regulatory T cells. Increased levels of inflammatory cells were coupled with elevated expression of cytokines such as TNFα, IFNγ and IL1β. We conclude that FGF21 acts to limit islet hyperplasia and may also prevent pancreatic inflammation.

Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution

Age-related thymic degeneration is associated with loss of naïve T cells, restriction of peripheral T-cell diversity, and reduced healthspan due to lower immune competence. The mechanistic basis of age-related thymic demise is unclear, but prior evidence suggests that caloric restriction (CR) can slow thymic aging by maintaining thymic epithelial cell integrity and reducing the generation of intrathymic lipid. Here we show that the prolongevity ketogenic hormone fibroblast growth factor 21 (FGF21), a member of the endocrine FGF subfamily, is expressed in thymic stromal cells along with FGF receptors and its obligate coreceptor, βKlotho. We found that FGF21 expression in thymus declines with age and is induced by CR. Genetic gain of FGF21 function in mice protects against age-related thymic involution with an increase in earliest thymocyte progenitors and cortical thymic epithelial cells. Importantly, FGF21 overexpression reduced intrathymic lipid, increased perithymic brown adipose tissue, and elevated thymic T-cell export and naïve T-cell frequencies in old mice. Conversely, loss of FGF21 function in middle-aged mice accelerated thymic aging, increased lethality, and delayed T-cell reconstitution postirradiation and hematopoietic stem cell transplantation (HSCT). Collectively, FGF21 integrates metabolic and immune systems to prevent thymic injury and may aid in the reestablishment of a diverse T-cell repertoire in cancer patients following HSCT.

REV-ERBα regulates Fgf21 expression in the liver via hepatic nuclear factor 6.

ABSTRACTThe circadian clock contributes to the timing of many body functions including metabolism and reproduction. The hepatokine fibroblast growth factor 21 (FGF21) is a critical metabolic regulator involved in modulation of fertility. Here we show that lack of the clock component REV-ERBα elevates FGF21 levels in liver and plasma. At the molecular level, REV-ERBα modulates the expression of FGF21 via the liver-specific hepatic nuclear factor 6 (HNF6). We conclude that REV-ERBα regulates metabolism and reproduction, at least in part, via regulation of Fgf21.

Differentiated embryo chondrocyte 1 (DEC1) is a novel negative regulator of hepatic fibroblast growth factor 21 (FGF21) in aging mice

Human differentiated embryo chondrocyte expressed gene 1 (DEC1) is frequently used as a marker of senescence in vivo. Fibroblast growth factor 21 (FGF21), a novel endocrine-like member of the FGF superfamily, is highly expressed in the liver, and FGF21-transgenic mice have extended lifespans. Thus, we hypothesized that FGF21 may play a role in the DEC1-mediated aging process. In this study, DEC1 knockout (KO) mice were used to characterize the mechanism by which FGF21 protects mice from aging. Aging is strongly diminished in DEC1 KO mice, which is reflected by decreased lipid levels and oxidative stress, leading to an amelioration of liver function and structure. The expression of FGF21 decreased with aging in wild-type (WT) mice, whereas ATF4, Phospho-ERK and Phospho-p38 expression was maintained and was accompanied by a compensatory rise of FGF21 mRNA and protein expression in DEC1 KO mice. Over-expression of DEC1 markedly abolished the hepatic expression of FGF21, and siRNA-mediated inhibition of endogenous DEC1 increased the expression of FGF21. DEC1 further diminished the expression of ATF4 in HepG2 cells over-expressing DEC1. The induction of FGF21 and ATF4 at the mRNA and protein levels during the course of aging supports the view that DEC1 KO mice are able to restore the age-related imbalance of metabolism. Collectively, the data obtained in this study suggest that DEC1 is a novel negative regulator of hepatic FGF21 expression.

Pharmacologic stimulation of central GLP-1 receptors has opposite effects on the alterations of plasma FGF21 levels induced by feeding and fasting

Fibroblast growth factor 21 (FGF21) functions as an endocrine hormone to regulate energy metabolism. Circulating FGF21 is derived from the liver and is produced in response to alterations of nutritional status. Here we show the effects of liraglutide, a human glucagon-like-peptide-1 (GLP-1) receptor agonist, injected into the third cerebral ventricle on body weight and plasma FGF21 levels in free-feeding mice, food-deprived mice, and mice provided 1g after the injection. In free-feeding mice, liraglutide (5–100μg/kg) injected into the third cerebral ventricle suppressed food intake and body weight after 24h in a dose-dependent manner. Liraglutide (50 and 100μg/kg) significantly increased plasma FGF21 levels and hepatic FGF21 expression, whereas smaller doses (5 and 10μg/kg) had no effect. In food-deprived mice, body weight did not differ significantly between the saline control and liraglutide-treated groups, but liraglutide (100μg/kg) significantly decreased plasma FGF21 levels at 24h compared with the saline control. In mice provided 1g food, body weight did not differ significantly between the saline control and liraglutide-treated groups, but liraglutide (50μg/kg) significantly decreased plasma FGF21 levels at 24h compared with the saline control. These findings suggest that intracerebral injection of liraglutide decreases body weight by inhibiting food intake and increases plasma FGF21 levels in free-feeding mice, whereas it suppresses the elevations of plasma FGF21 levels induced by fasting or the restricted feeding. Thus, pharmacologic stimulation of central GLP-1 receptors has opposite effects on the alterations of plasma FGF21 levels induced by feeding and fasting.

Skeletal muscle-specific eukaryotic translation initiation factor 2α phosphorylation controls amino acid metabolism and fibroblast growth factor 21-mediated non-cell-autonomous energy metabolism.

The eukaryotic translation initiation factor 2α (eIF2α) phosphorylation-dependent integrated stress response (ISR), a component of the unfolded protein response, has long been known to regulate intermediary metabolism, but the details are poorly worked out. We report that profiling of mRNAs of transgenic mice harboring a ligand-activated skeletal muscle–specific derivative of the eIF2α protein kinase R-like ER kinase revealed the expected up-regulation of genes involved in amino acid biosynthesis and transport but also uncovered the induced expression and secretion of a myokine, fibroblast growth factor 21 (FGF21), that stimulates energy consumption and prevents obesity. The link between the ISR and FGF21 expression was further reinforced by the identification of a small-molecule ISR activator that promoted Fgf21 expression in cell-based screens and by implication of the ISR-inducible activating transcription factor 4 in the process. Our findings establish that eIF2α phosphorylation regulates not only cell-autonomous proteostasis and amino acid metabolism, but also affects non–cell-autonomous metabolic regulation by induced expression of a potent myokine.—Miyake, M., Nomura, A., Ogura, A., Takehana, K., Kitahara, Y., Takahara, K., Tsugawa, K., Miyamoto, C., Miura, N., Sato, R., Kurahashi, K., Harding, H. P., Oyadomari, M., Ron, D., Oyadomari, S. Skeletal muscle–specific eukaryotic translation initiation factor 2α phosphorylation controls amino acid metabolism and fibroblast growth factor 21–mediated non–cell-autonomous energy metabolism.

Alterations in Hepatic FGF21, Co-Regulated Genes, and Upstream Metabolic Genes in Response to Nutrition, Ketosis and Inflammation in Peripartal Holstein Cows.

In rodents, fibroblast growth factor 21 (FGF21) has emerged as a key metabolic regulator produced by liver. To gather preliminary data on the potential importance of FGF1, co-regulated genes, and upstream metabolic genes, we examined the hepatic mRNA expression in response to nutrition and inflammation in dairy cows. In experiment 1, induction of ketosis through feed restriction on d 5 postpartum upregulated FGF21, its co-receptor KLB, and PPARA but only elicited a numerical increase in serum FGF21 concentration. In experiment 2, cows in control (CON) or receiving 50 g/d of L-carnitine (C50) from -14 through 21 d had increased FGF21, PPARA, and NFIL3 on d 10 compared with d 2 postpartum. In contrast, compared with CON and C50, 100 g/d L-carnitine (C100) resulted in lower FGF21, KLB, ANGPTL4, and ARNTL expression on d 10. In experiment 3, cows were fed during the dry period either a higher-energy (OVE; 1.62 Mcal/kg DM) or lower-energy (CON; 1.34 Mcal/kg DM) diet and received 0 (OVE:N, CON:N) or 200 μg of LPS (OVE:Y, CON:Y) into the mammary gland at d 7 postpartum. For FGF21 mRNA expression in CON, the LPS challenge (CON:Y) prevented a decrease in expression between d 7 and 14 postpartum such that cows in CON:N had a 4-fold lower expression on d 14 compared with d 7. The inflammatory stimulus induced by LPS in CON:Y resulted in upregulation of PPARA on d 14 to a similar level as cows in OVE:N. In OVE:Y, expression of PPARA was lower than CON:N on d 7 and remained unchanged on d 14. On d 7, LPS led to a 4-fold greater serum FGF21 only in OVE but not in CON cows. In fact, OVE:Y reached the same serum FGF21 concentration as CON:N, suggesting a carryover effect of dietary energy level on signaling mechanisms within liver. Overall, results indicate that nutrition, ketosis, and inflammation during the peripartal period can alter hepatic FGF21, co-regulated genes, and upstream metabolic genes to various extents. The functional outcome of these changes merits further study, and in particular the mechanisms regulating transcription in response to changes in energy balance and feed intake.

Short-Term Curcumin Gavage Sensitizes Insulin Signaling in Dexamethasone-Treated C57BL/6 Mice1–3

Background: Long-term dietary curcumin (>12 wk) improves metabolic homeostasis in obese mice by sensitizing insulin signaling and reducing hepatic gluconeogenesis. Whether these occur only secondary to its chronic anti-inflammatory and antioxidative functions is unknown.Objective: In this study, we assessed the insulin sensitization effect of short-term curcumin gavage in a rapid dexamethasone-induced insulin resistance mouse model, in which the chronic anti-inflammatory function is eliminated.Methods: Six-week-old male C57BL/6 mice received an intraperitoneal injection of dexamethasone (100 mg/kg body weight) or phosphate-buffered saline every day for 5 d, with or without simultaneous curcumin gavage (500 mg/kg body weight). On day 7, insulin tolerance tests were performed. After a booster dexamethasone injection and curcumin gavage on day 8, blood glucose and insulin concentrations were measured. Liver tissues were collected on day 10 for quantitative polymerase chain reaction and Western blotting to assess gluconeogenic gene expression, insulin signaling, and the expression of fibroblast growth factor 21 (FGF21). Primary hepatocytes from separate, untreated C57BL/6 mice were used for testing the in vitro effect of curcumin treatment.Results: Dexamethasone injection impaired insulin tolerance (P < 0.05) and elevated ambient plasma insulin concentrations by ∼2.7-fold (P < 0.01). Concomitant curcumin administration improved insulin sensitivity and reduced hepatic gluconeogenic gene expression. The insulin sensitization effect of curcumin was demonstrated by increased stimulation of S473 phosphorylation of protein kinase B (P < 0.01) in the dexamethasone-treated mouse liver, as well as the repression of glucose production in primary hepatocytes (P < 0.001). Finally, curcumin gavage increased FGF21 expression by 2.1-fold in the mouse liver (P < 0.05) and curcumin treatment increased FGF21 expression in primary hepatocytes.Conclusion: These observations suggest that the early beneficial effect of curcumin intervention in dexamethasone-treated mice is the sensitization of insulin signaling, involving the stimulation of FGF21 production, a known insulin sensitizer.

Research Perspectives on the Regulation and Physiological Functions of FGF21 and its Association with NAFLD.

Fibroblast growth factor 21 (FGF21) is a metabolic hormone primarily secreted from the liver and functions in multiple tissues. Various transcription factors induce FGF21 expression in the liver, which indicates that FGF21 is a mediator of multiple environmental cues. FGF21 alters metabolism under starvation conditions, protects the body from energy depletion, and extends life span. Pharmacological administration of FGF21 alleviates dyslipidemia and induces weight loss in obese animals. In addition to the well-studied functions of FG21, several lines of recent evidence indicate a possible link between FGF21 and non-alcoholic fatty liver disease (NAFLD). High serum levels of FGF21 are associated with NAFLD and its risk factors, such as endoplasmic reticulum stress and chronic inflammation. In addition, FGF21 alleviates the major risk factors of NAFLD, including obesity, dyslipidemia, and insulin insensitivity. Thus, FGF21 is a potential drug candidate for diseases, such as NAFLD, dyslipidemia, and type 2 diabetes. In this review, the research perspectives of FGF21 and therapeutic potencies of FGF21 as a modulator of NAFLD are summarized.

FGF21 and Cardiac Physiopathology.

The heart is not traditionally considered either a target or a site of fibroblast growth factor-21 (FGF21) production. However, recent findings indicate that FGF21 can act as a cardiomyokine; that is, it is produced by cardiac cells at significant levels and acts in an autocrine manner on the heart itself. The heart is sensitive to the effects of FGF21, both systemic and locally generated, owing to the expression in cardiomyocytes of β-Klotho, the key co-receptor known to confer specific responsiveness to FGF21 action. FGF21 has been demonstrated to protect against cardiac hypertrophy, cardiac inflammation, and oxidative stress. FGF21 expression in the heart is induced in response to cardiac insults, such as experimental cardiac hypertrophy and myocardial infarction in rodents, as well as in failing human hearts. Intracellular mechanisms involving PPARα and Sirt1 mediate transcriptional regulation of the FGF21 gene in response to exogenous stimuli. In humans, circulating FGF21 levels are elevated in coronary heart disease and atherosclerosis, and are associated with a higher risk of cardiovascular events in patients with type 2 diabetes. These findings provide new insights into the role of FGF21 in the heart and may offer potential therapeutic strategies for cardiac disease.

Disruption of mitochondrial fission in the liver protects mice from diet-induced obesity and metabolic deterioration.

Mitochondria and the endoplasmic reticulum (ER) physically interact by close structural juxtaposition, via the mitochondria-associated ER membrane. Inter-organelle communication between the ER and mitochondria has been shown to regulate energy metabolism and to be central to the modulation of various key processes such as ER stress. We aimed to clarify the role of mitochondrial fission in this communication. We generated mice lacking the mitochondrial fission protein dynamin-related protein 1 (DRP1) in the liver (Drp1LiKO mice). Drp1LiKO mice showed decreased fat mass and were protected from high-fat diet (HFD)-induced obesity. Analysis of liver gene expression profiles demonstrated marked elevation of ER stress markers. In addition, we observed increased expression of the fibroblast growth factor 21 (FGF21) gene through induction of activating transcription factor 4, master regulator of the integrated stress response. Disruption of mitochondrial fission in the liver provoked ER stress, while inducing the expression of FGF21 to increase energy expenditure and protect against HFD-induced obesity.

The modulating effect of Persea americana fruit extract on the level of expression of fatty acid synthase complex, lipoprotein lipase, fibroblast growth factor-21 and leptin – A biochemical study in rats subjected to experimental hyperlipidemia and obesity

BackgroundObesity is a multifactorial disorder which is closely associated with hyperlipidemia. Avocados are edible fruits traditionally consumed for various health benefits including body weight reduction. Hypothesis/purposeTo determine the hypolipidemic and anti-obesity effect of hydro-alcoholic fruit extract of avocado (HFEA) in rats fed with high fat diet (HFD). Study designMale Sprague Dawley rats were divided into four groups. Groups 1 and 2 rats were fed with normal diet. Groups 3 and 4 rats were fed with HFD for 14 weeks. In addition, Groups 2 and 4 rats were co-administered with 100 mg/kg body weight of HFEA from 3rd week onwards. MethodsThe HFEA was subjected to HPLC to quantify the major phytonutrients. Body mass index (BMI), adiposity index (ADI), total fat pad mass (TFP), blood lipid levels were determined in all the groups of rats. The mRNA expression of fatty acid synthase (FASN), lipoprotein lipase (LPL), fibroblast growth factor 21 (FGF21) and leptin was also assessed. ResultsHFEA was found to contain flavonoids: rutin-141.79, quercetin-5.25, luteolin-165, phenolic compounds: gallic acid-198.57, ellagic acid-238.22, vanillic acid-4.79 and phytosterols: betasitosterol-70, stigmasterol-12.5 (mg/100 g). HFEA reduced BMI, ADI, TFP, blood cholesterol, triglycerides, and LDL in rats fed with HFD. Serum leptin was found reduced in HFEA co-administered rats. The mRNA expression of FASN, LPL, and leptin in subcutaneous and visceral adipose tissue was found to be significantly reduced in HFEA co-administered rats. The gene expression of fibroblast growth factor-21 (FGF21) was found to be significantly increased in HFEA treated rats when compared to HFD control rats. ConclusionThe hypolipidemic effect of HFEA may be partly due to its modulating effect on endogenous fat synthesis and adiponectin formation through the transcription factor FGF21. The results also show that avocado fruit extract has profound influence on leptin activity, which controls satiety and hunger to regulate the food intake.

Role of Fibroblast Growth Factor 21 (FGF21) in the Regulation of Statural Growth

In this review, we discuss the evidence supporting the causative role of increased FGF21 expression in reduced GH action and impaired longitudinal bone growth. Fibroblast Growth Factor (FGF) 21 (FGF21) is a member of a subfamily of FGFs which lack the FGF heparin-binding domain. Thus, these FGFs can function as endocrine as well as paracrine factors. During fasting, increased expression of FGF21 induces gluconeogenesis, fatty acid oxidation, and ketogenesis: as a result, FGF21 is considered a key regulator of the metabolic adaptation to fasting. In addition, recent evidence indicates that FGF21 may regulate longitudinal bone growth. It has been shown that transgenic mice overexpressing FGF21 exhibit reduced bone growth and hepatic Growth Hormone (GH) insensitivity. FGF21 knock-out mice exposed to chronic food restriction experience greater body and tibial growth than their food-restricted wild-type littermates, suggesting that the increased FGF21 expression in wild-type mice during undernutrition leads to reduced skeletal growth. The FGF21-mediated attenuation of bone growth appears to be secondary to reduced GH sensitivity, both systemically and locally in the long bones' growth plate. The effects of FGF21 on GH action are direct, and may result from the reduced translocation of GH receptors from the cytoplasm to the cell membrane. Lastly, we discuss recent studies which have shown that FGF21 in infancy is inversely correlated with linear growth rate. In conclusion, all the evidence discussed in this review indicates that FGF21 may be an important negative regulator of mammalian growth.

177. Recapitulating the Triglyceride-Lowering Effect of Cold Exposure By Overexpression of Fibroblast Growth Factor-21 Gene

Cold exposure reduces blood triglyceride level via repressing lipid synthesis and enhancing lipid oxidation, providing a potential option for hyperlipidemia therapy. However, cold exposure is not a practical therapeutic approach in humans due to its unacceptable requirements. As the effect of cold exposure is associated with elevated expression of fibroblast growth factor-21 (Fgf21) in the liver and brown adipose tissue (BAT), we assessed in this study whether the metabolic benefits of cold exposure in lowering blood triglyceride can be recapitulated by overexpressing Fgf21. Overexpression of Fgf21 was achieved by hydrodynamic delivery of plasmid driven by an albumin promoter for Fgf21 expression. Our results show that hydrodynamic transfer of the Fgf21 plasmid exclusively elevated Fgf21 expression in the liver in a dose-dependent manner. Fgf21 overexpression greatly improves triglyceride metabolism in regular as well as high-fat diet-induced obese mice, as evidenced by improved profiles of oral fat tolerance tests and reduced fasting triglyceride levels in blood. Mechanistically, improvements in triglyceride metabolism mediated by Fgf21 transfer were achieved by repressed lipid synthesis in the liver and enhanced lipid oxidation in BAT. At the molecular level, Fgf21 transfer repressed transcription of a variety of pivotal genes involved in lipid synthesis in liver, including Srebp1c, Fas, Scd1, Ppargamma2 and Mgat1, while increasing mRNA levels of Cpt1-alpha and Acadl, suggesting that the hepatic lipid synthesis was repressed while oxidation enhanced. In fact, transfer of the Fgf21 remained effective in attenuating hyperlipidemia in mice fed with 30% fructose and injected with lipase inhibitor, further verifying that this genetic approach markedly diminished hepatic lipid synthesis. In BAT, Fgf21 transfer induced a “super-brown” phenotypic change, which was accompanied by elevated expression of a panel of vital genes for adaptive thermogenesis, such as Ucp1, Pgc1-alpha, Cidea, Dio2 and Elovl3. Collectively, our findings unveil that the triglyceride-lowering effect of cold exposure can be fully recapitulated by liver-specific delivery of the Fgf21 using a hydrodynamics-based procedure, indicating that this new approach may provide an alternative and more acceptable option for hyperlipidemia therapy in humans.

Skeletal muscle increases FGF21 expression in mitochondrial disorders to compensate for energy metabolic insufficiency by activating the mTOR–YY1–PGC1α pathway

Fibroblast growth factor 21 (FGF21) is a growth factor with pleiotropic effects on regulating lipid and glucose metabolism. Its expression is increased in skeletal muscle of mice and humans with mitochondrial disorders. However, the effects of FGF21 on skeletal muscle in response to mitochondrial respiratory chain deficiency are largely unknown. Here we demonstrate that the increased expression of FGF21 is a compensatory response to respiratory chain deficiency. The mRNA and protein levels of FGF21 were robustly raised in skeletal muscle from patients with mitochondrial myopathy or MELAS. The mammalian target of rapamycin (mTOR) phosphorylation levels and its downstream targets, Yin Yang 1 (YY1) and peroxisome proliferator-activated receptor γ, coactivator 1α (PGC-1α), were increased by FGF21 treatment in C2C12 myoblasts. Activation of the mTOR–YY1–PGC1α pathway by FGF21 in myoblasts regulated energy homeostasis as demonstrated by significant increases in intracellular ATP synthesis, oxygen consumption rate, activity of citrate synthase, glycolysis, mitochondrial DNA copy number, and induction of the expression of key energy metabolic genes. The effects of FGF21 on mitochondrial function required phosphoinositide 3-kinase (PI3K), which activates mTOR. Inhibition of PI3K, mTOR, YY1, and PGC-1α activities attenuated the stimulating effects of FGF21 on intracellular ATP levels and mitochondrial gene expression. Our findings revealed that mitochondrial respiratory chain deficiency elicited a compensatory response in skeletal muscle by increasing the FGF21 expression levels in muscle, which resulted in enhanced mitochondrial function through an mTOR–YY1–PGC1α-dependent pathway in skeletal muscle.

FGF21 Mediates Alcohol‐Induced Adipose Tissue Lipolysis by Activation of Systemic Release of Catecholamine in Mice

Alcohol consumption leads to adipose tissue lipoatrophy and mobilization of free fatty acids (FFA), which contributes to hepatic fat accumulation in alcoholic liver disease (ALD). Fibroblast growth factor 21 (FGF21) is a metabolic regulator and plays an important role in glucose and lipid homeostasis in various diseases. Here, we demonstrate that FGF21 knockout (KO) mice are resistant to chronic‐binge alcohol exposure‐induced epididymal white adipose tissue lipolysis. Alcohol consumption increases FGF21 expression both in the liver and adipose tissue. Alcohol exposure causes adipose intracellular cAMP elevation, and lipolytic enzymes and coating protein activation, leading to FFA mobilization in both wild type and FGF21 KO mice. However, alcohol‐induced systemic elevation of catecholamine release, which is known to be a major player in adipose lipolysis by binding to the β‐adrenergic receptor and subsequently PKA activation, was markedly inhibited in KO mice. Supplementation with recombinant human FGF21 to alcohol‐exposed KO mice caused increased fat loss in parallel with an increase of circulating norepinephrine concentration. Furthermore, alcohol consumption‐induced fatty liver is blunted in the KO mice, indicating an inhibition of fatty acid reverse transport from adipose to the liver in the KO mice. In conclusion: FGF21 deficient mice are protected from alcohol‐induced adipose tissue excess‐lipolysis through a mechanism involving sympathetic nervous system (SNS) activation and catecholamine release. Strategies targeting the SNS activation to block FGF21‐mediated excess‐adipose lipolysis might be developed to prevent/treat alcohol‐induced fatty liver disease.

Placental fibroblast growth factor 21 is not altered in late-onset preeclampsia.

BackgroundPreeclampsia (PE) is associated with alterations of placental function. The incidence of PE is higher in insulin resistant states. Women with PE have high circulating levels of the metabolic regulator fibroblast growth factor 21 (FGF21). FGF21 is synthesized in the placenta. The aim of this study was to compare the expression of FGF21, its receptors, downstream targets and transcriptional regulators in placental tissue from pregnancies with and without late-onset PE. Circulating FGF21 in maternal and cord blood was also studied.MethodsmRNA expression was determined by semi-quantitative real-time PCR and normalized for cellular composition in 17 women with and 20 without PE. Protein expression was quantified by Western Blot. FGF21 levels were measured by ELISA in maternal and cord serum of ten mother-baby dyads per condition.ResultsPlacental FGF21 mRNA and protein expression were similar in PE compared with control. Placental mRNA expression of the FGF receptors (1–4) and the co-receptor beta-Klotho was not different between the groups. There was no difference in the expression of the glucose transporters GLUT1, 3 or 4. PPAR-alpha but not PPAR-gamma expression was decreased in PE. Maternal FGF21 serum levels were not significantly different in PE. FGF21 was detected in cord blood of 6 infants (4 PE, 2 controls) but was undetectable in 14 infants.ConclusionsLate-onset PE is not associated with major changes to the expression of FGF21, its receptors or metabolic targets.Electronic supplementary materialThe online version of this article (doi:10.1186/s12958-015-0006-3) contains supplementary material, which is available to authorized users.

Role of fibroblast growth factor 21 in the early stage of NASH induced by methionine- and choline-deficient diet

Fibroblast growth factor 21 (FGF21) is a modulator of energy homeostasis and is increased in human nonalcoholic liver disease (NAFLD) and after feeding of methionine- and choline-deficient diet (MCD), a conventional inducer of murine nonalcoholic steatohepatitis (NASH). However, the significance of FGF21 induction in the occurrence of MCD-induced NASH remains undetermined. C57BL/6J Fgf21-null and wild-type mice were treated with MCD for 1week. Hepatic Fgf21 mRNA was increased early after commencing MCD treatment independent of peroxisome proliferator-activated receptor (PPAR) α and farnesoid X receptor. While no significant differences in white adipose lipolysis were seen in both genotypes, hepatic triglyceride (TG) contents were increased in Fgf21-null mice, likely due to the up-regulation of genes encoding CD36 and phosphatidic acid phosphatase 2a/2c, involved in fatty acid (FA) uptake and diacylglycerol synthesis, respectively, and suppression of increased mRNAs encoding carnitine palmitoyl-CoA transferase 1α, PPARγ coactivator 1α, and adipose TG lipase, which are associated with lipid clearance in the liver. The MCD-treated Fgf21-null mice showed increased hepatic endoplasmic reticulum (ER) stress. Exposure of primary hepatocytes to palmitic acid elevated the mRNA levels encoding DNA damage-inducible transcript 3, an indicator of ER stress, and FGF21 in a PPARα-independent manner, suggesting that lipid-induced ER stress can enhance hepatic FGF21 expression. Collectively, FGF21 is elevated in the early stage of MCD-induced NASH likely to minimize hepatic lipid accumulation and ensuing ER stress. These results provide a possible mechanism on how FGF21 is increased in NAFLD/NASH.

Fibroblast growth factor 21 participates in adaptation to endoplasmic reticulum stress and attenuates obesity-induced hepatic metabolic stress.

Fibroblast growth factor 21 (FGF21) is an endocrine hormone that exhibits anti-diabetic and anti-obesity activity. FGF21 expression is increased in patients with and mouse models of obesity or nonalcoholic fatty liver disease (NAFLD). However, the functional role and molecular mechanism of FGF21 induction in obesity or NAFLD are not clear. As endoplasmic reticulum (ER) stress is triggered in obesity and NAFLD, we investigated whether ER stress affects FGF21 expression or whether FGF21 induction acts as a mechanism of the unfolded protein response (UPR) adaptation to ER stress induced by chemical stressors or obesity. Hepatocytes or mouse embryonic fibroblasts deficient in UPR signalling pathways and liver-specific eIF2α mutant mice were employed to investigate the in vitro and in vivo effects of ER stress on FGF21 expression, respectively. The in vivo importance of FGF21 induction by ER stress and obesity was determined using inducible Fgf21-transgenic mice and Fgf21-null mice with or without leptin deficiency. We found that ER stressors induced FGF21 expression, which was dependent on a PKR-like ER kinase-eukaryotic translation factor 2α-activating transcription factor 4 pathway both in vitro and in vivo. Fgf21-null mice exhibited increased expression of ER stress marker genes and augmented hepatic lipid accumulation after tunicamycin treatment. However, these changes were attenuated in inducible Fgf21-transgenic mice. We also observed that Fgf21-null mice with leptin deficiency displayed increased hepatic ER stress response and liver injury, accompanied by deteriorated metabolic variables. Our results suggest that FGF21 plays an important role in the adaptive response to ER stress- or obesity-induced hepatic metabolic stress.

Thyroid hormone receptor regulates most genes independently of fibroblast growth factor 21 in liver.

Thyroid hormone (TH) acts through specific receptors (TRs), which are conditional transcription factors, to induce fibroblast growth factor 21 (FGF21), a peptide hormone that is usually induced by fasting and that influences lipid and carbohydrate metabolism via local hepatic and systemic endocrine effects. While TH and FGF21 display overlapping actions when administered, including reductions in serum lipids, according to the current models these hormones act independently in vivo. In this study, we examined mechanisms of regulation of FGF21 expression by TH and tested the possibility that FGF21 is required for induction of hepatic TH-responsive genes. We confirm that active TH (triiodothyronine (T3)) and the TRβ-selective thyromimetic GC1 increase FGF21 transcript and peptide levels in mouse liver and that this effect requires TRβ. T3 also induces FGF21 in cultured hepatocytes and this effect involves direct actions of TRβ1, which binds a TRE within intron 2 of FGF21. Gene expression profiles of WT and Fgf21-knockout mice are very similar, indicating that FGF21 is dispensable for the majority of hepatic T3 gene responses. A small subset of genes displays diminished T3 response in the absence of FGF21. However, most of these are not obviously directly involved in T3-dependent hepatic metabolic processes. Consistent with these results, T3-dependent effects on serum cholesterol are maintained in the Fgf21(-/-) background and we observe no effect of the Fgf21-knockout background on serum triglycerides and glucose. Our findings indicate that T3 regulates the genes involved in classical hepatic metabolic responses independently of FGF21.