Targeting the FGF19-FGFR4 pathway for cholestatic, metabolic, and cancerous diseases.

Human fibroblast growth factor 19 (FGF19, or FGF15 in rodents) plays a central role in controlling bile acid (BA) synthesis through a negative feedback mechanism. This process involves a postprandial crosstalk between the BA-activated ileal farnesoid X receptor and the hepatic Klotho beta (KLB) coreceptor complexed with fibrobalst growth factor receptor 4 (FGFR4) kinase. Additionally, FGF19 regulates glucose, lipid, and energy metabolism by coordinating responses from functional KLB and FGFR1-3 receptor complexes on the periphery.

Activity-balanced GLP-1/GDF15 dual agonist reduces body weight and metabolic disorder in mice and non-human primates.

Obesity is a considerable health concern with limited pharmacotherapy options of low efficacy. Here, we develop a GLP-1/GDF15 fusion protein and explore its weight-lowering potential in animals. The molecule, QL1005, is engineered via fusing GLP-1 and GDF15 analogs by a peptide linker and conjugating it to a fatty acid for time-action extension.

Glucagon receptor signaling regulates weight loss via central KLB receptor complexes.

Glucagon regulates glucose and lipid metabolism and promotes weight loss. Thus, therapeutics stimulating glucagon receptor (GCGR) signaling are promising for obesity treatment; however, the underlying mechanism(s) have yet to be fully elucidated. We previously identified that hepatic GCGR signaling increases circulating fibroblast growth factor 21 (FGF21), a potent regulator of energy balance.

FGF19 and FGF21: In NASH we trust.

Objective: FGF19 and FGF21 have shown therapeutic promise since their discovery, attested by the fact there are at least 5 assets that activate the FGFR/KLB pathway and one FGF19 analog in clinical development.

Methods: We performed a detailed analyses of published preclinical and clinical data to offer insights into the mechanism of action, as well as PK/PD and efficacy data of the clinical assets.

Results: Scouring the literature, we offer mechanistic insights from preclinical data using rodents and non-human primates and pharmacodynamic data from clinical studies.

Optimization of Peptide Inhibitors of β-Klotho as Antagonists of Fibroblast Growth Factors 19 and 21.

Fibroblast growth factors 19 and 21 (FGF19 and FGF21) have biological actions that render them promising clinical candidates for treatment of metabolic diseases, particularly dyslipidemia and nonalcoholic steatohepatitis (NASH). These two atypical endocrine FGFs employ an accessory receptor β-klotho (KLB) to signal through classical FGF receptors (FGFRs). FGF19 and FGF21 bind to KLB via their C-terminus, to orient the N-terminus for productive interaction with FGFRs.

Molecular elements in FGF19 and FGF21 defining KLB/FGFR activity and specificity.

Objective: To signal, FGF19 and FGF21 require co-receptor βKlotho (KLB) to act in concert with FGF receptors, and yet there is appreciable variance in the C-terminal sequences of these two novel metabolic hormones where binding is believed to be primary. We seek to determine the functional consequences for these amino acid differences and determine whether such information can be used to design high potency antagonists and agonists.

Methods: We employed a functional in vitro assay to identify C-terminal protein fragments capable of fully blocking KLB-mediated FGF19 and 21 receptor signaling.

Cholic Acid Supplementation of a High-Fat Obesogenic Diet Suppresses Hepatic Triacylglycerol Accumulation in Mice via a Fibroblast Growth Factor 21-Dependent Mechanism.

Background: Supplementation of a high-fat obesogenic diet (HFD) with cholic acid (CA) suppresses the development of obesity, insulin resistance, and hepatic steatosis in mice.

Objective: We investigated the role of fibroblast growth factor 21 (FGF21) in mediating the beneficial actions of CA on metabolic syndrome.

Methods: Male 7-wk-old wild-type (WT) mice and FGF21 knockout (FGF21KO) mice were fed an HFD for 12 wk followed by a 4-wk period in which the mice were fed the HFD alone or supplemented with 0.

Fibroblast activation protein (FAP) as a novel metabolic target.

Objective: Fibroblast activation protein (FAP) is a serine protease belonging to a S9B prolyl oligopeptidase subfamily. This enzyme has been implicated in cancer development and recently reported to regulate degradation of FGF21, a potent metabolic hormone. Using a known FAP inhibitor, talabostat (TB), we explored the impact of FAP inhibition on metabolic regulation in mice.

The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling.

FGF21 is an atypical member of the FGF family that functions as a hormone to regulate carbohydrate and lipid metabolism. Here we demonstrate that the actions of FGF21 in mouse adipose tissue, but not in liver, are modulated by the nuclear receptor Rev-erbα, a potent transcriptional repressor. Interrogation of genes induced in the absence of Rev-erbα for Rev-erbα-binding sites identified βKlotho, an essential coreceptor for FGF21, as a direct target gene of Rev-erbα in white adipose tissue but not liver.

Overexpression of β-Klotho in Adipose Tissue Sensitizes Male Mice to Endogenous FGF21 and Provides Protection From Diet-Induced Obesity.

The endocrine hormone fibroblast growth factor 21 (FGF21) is induced in the adaptive response to nutrient deprivation, where it serves to regulate the integrated response to fasting via its primary receptor complex, FGF receptor 1 coupled with the cofactor β-klotho (KLB) in target tissues. Curiously, endogenous FGF21 levels are also elevated in preclinical models of obesity and in obese/diabetic individuals. In addition to higher FGF21 levels, reduced KLB expression in liver and adipose tissue has been noted in these same individuals, suggesting that obesity may represent an FGF21 resistant state.

FGF21 Revolutions: Recent Advances Illuminating FGF21 Biology and Medicinal Properties.

The biology of fibroblast growth factor 21 (FGF21) has evolved through its first decade at a revolutionary pace with dramatic refinements in this relatively short span of time. This field is poised now with a deeper understanding of its specific physiological role, pathological ramifications for its inappropriate function, and a much-enriched context of the complex hormonal network in which it serves to regulate metabolism. As a derivative of these discoveries, the application of FGF21 as a medicinal agent has emerged with structurally optimized protein-based analogs being preclinically explored in multiple species, and, more recently, through clinical studies.

Dual effects of fibroblast growth factor 21 on hepatic energy metabolism.

The aim of this study was to investigate the mechanisms by which fibroblast growth factor 21 (FGF21) affects hepatic integration of carbohydrate and fat metabolism in Siberian hamsters, a natural model of adiposity. Twelve aged matched adult male Siberian hamsters maintained in their long-day fat state since birth were randomly assigned to one of two treatment groups and were continuously infused with either vehicle (saline; n=6) or recombinant human FGF21 protein (1 mg/kg per day; n=6) for 14 days. FGF21 administration caused a 40% suppression (P<0.

Genetic disruption of uncoupling protein 1 in mice renders brown adipose tissue a significant source of FGF21 secretion.

Objective: Circulating fibroblast growth factor 21 (FGF21) is an important auto- and endocrine player with beneficial metabolic effects on obesity and diabetes. In humans, thermogenic brown adipose tissue (BAT) was recently suggested as a source of FGF21 secretion during cold exposure. Here, we aim to clarify the role of UCP1 and ambient temperature in the regulation of FGF21 in mice.

Discrete Aspects of FGF21 In Vivo Pharmacology Do Not Require UCP1.

A primary target of the pleiotropic metabolic hormone FGF21 is adipose tissue, where it initiates a gene expression program to enhance energy expenditure, an effect presumed to be centered on augmented UCP1 expression and activity. In UCP1 null (UCP1KO) mice, we show that the effect of FGF21 to increase the metabolic rate is abolished. However, in contrast to prior expectations, we found that increased UCP1-dependent thermogenesis is only partially required to achieve the beneficial effects of FGF21 treatment.

Central Fibroblast Growth Factor 21 Browns White Fat via Sympathetic Action in Male Mice.

Fibroblast growth factor 21 (FGF21) has multiple metabolic actions, including the induction of browning in white adipose tissue. Although FGF21 stimulated browning results from a direct interaction between FGF21 and the adipocyte, browning is typically associated with activation of the sympathetic nervous system through cold exposure. We tested the hypothesis that FGF21 can act via the brain, to increase sympathetic activity and induce browning, independent of cell-autonomous actions.

Naringenin prevents obesity, hepatic steatosis, and glucose intolerance in male mice independent of fibroblast growth factor 21.

The molecular mechanisms and metabolic pathways whereby the citrus flavonoid, naringenin, reduces dyslipidemia and improves glucose tolerance were investigated in C57BL6/J wild-type mice and fibroblast growth factor 21 (FGF21) null (Fgf21(-/-)) mice. FGF21 regulates energy homeostasis and the metabolic adaptation to fasting. One avenue of this regulation is through induction of peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc1a), a regulator of hepatic fatty acid oxidation and ketogenesis.

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.

Break on through to the other 1.

Although discovered in 1974, FGF1 was previously unrealized to have a role in metabolism. Suh et al. (2014) now report impressive pharmacological outcomes of FGF1 therapy in mice that imply this protein is an important metabolic regulator with therapeutic potential in the treatment of insulin resistance and type 2 diabetes.

Fibroblast growth factor 21 limits lipotoxicity by promoting hepatic fatty acid activation in mice on methionine and choline-deficient diets.

Background & Aims: Nonalcoholic fatty liver disease is a common consequence of human and rodent obesity. Disruptions in lipid metabolism lead to accumulation of triglycerides and fatty acids, which can promote inflammation and fibrosis and lead to nonalcoholic steatohepatitis. Circulating levels of fibroblast growth factor (FGF)21 increase in patients with nonalcoholic fatty liver disease or nonalcoholic steatohepatitis; therefore, we assessed the role of FGF21 in the progression of murine fatty liver disease, independent of obesity, caused by methionine and choline deficiency.

Photoperiodic regulation of FGF21 production in the Siberian hamster.

This article is part of a Special Issue "Energy Balance". FGF21 is an endocrine member of the fibroblast growth factor superfamily that has been shown to play an important role in the physiological response to nutrient deprivation. Food restriction enhances hepatic FGF21 production, which serves to engage an integrated response to energy deficit.

Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR).

The toxic effects of dioxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), mainly through activation of the aryl hydrocarbon receptor (AhR) are well documented. Fibroblast growth factor (Fgf) 21 plays critical roles in metabolic adaptation to fasting by increasing lipid oxidation and ketogenesis in the liver. The present study was performed to determine whether activation of the AhR induces Fgf21 expression.