Fibroblast Growth Factor Type 1 Ameliorates High-Glucose-Induced Oxidative Stress and Neuroinflammation in Retinal Pigment Epithelial Cells and a Streptozotocin-Induced Diabetic Rat Model.

Diabetic retinopathy (DR) is a common complication of diabetes that causes severe visual impairment globally. The pathogenesis of DR is related to oxidative stress and chronic inflammation. The fibroblast growth factor type 1 (FGF-1) mitogen plays crucial roles in cell function, development, and metabolism. FGF-1 is involved in blood sugar regulation and exerts beneficial antioxidative and anti-inflammatory effects on various organ systems. This study investigated the antioxidative and anti-inflammatory neuroprotective effects of FGF-1 on high-glucose-induced retinal damage. The results revealed that FGF-1 treatment significantly reversed the harmful effects of oxidative stress and inflammatory mediators in retinal tissue in a streptozotocin-induced diabetic rat model. These protective effects were also observed in the in vitro model of retinal ARPE-19 cells exposed to a high-glucose condition. We demonstrated that FGF-1 attenuated p38 mitogen-activated protein kinase and nuclear factor-κB pathway activation under the high-glucose condition. Our results indicated that FGF-1 could effectively prevent retinal injury in diabetes. The findings of this study could be used to develop novel treatments for DR that aim to reduce the cascade of oxidative stress and inflammatory signals in neuroretinal tissue.

A PPARγ-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis.

Although feast and famine cycles illustrate that remodelling of adipose tissue in response to fluctuations in nutrient availability is essential for maintaining metabolic homeostasis, the underlying mechanisms remain poorly understood. Here we identify fibroblast growth factor 1 (FGF1) as a critical transducer in this process in mice, and link its regulation to the nuclear receptor PPARγ (peroxisome proliferator activated receptor γ), which is the adipocyte master regulator and the target of the thiazolidinedione class of insulin sensitizing drugs. FGF1 is the prototype of the 22-member FGF family of proteins and has been implicated in a range of physiological processes, including development, wound healing and cardiovascular changes. Surprisingly, FGF1 knockout mice display no significant phenotype under standard laboratory conditions. We show that FGF1 is highly induced in adipose tissue in response to a high-fat diet and that mice lacking FGF1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with a high-fat diet. Further analysis of adipose depots in FGF1-deficient mice revealed multiple histopathologies in the vasculature network, an accentuated inflammatory response, aberrant adipocyte size distribution and ectopic expression of pancreatic lipases. On withdrawal of the high-fat diet, this inflamed adipose tissue fails to properly resolve, resulting in extensive fat necrosis. In terms of mechanisms, we show that adipose induction of FGF1 in the fed state is regulated by PPARγ acting through an evolutionarily conserved promoter proximal PPAR response element within the FGF1 gene. The discovery of a phenotype for the FGF1 knockout mouse establishes the PPARγ­FGF1 axis as critical for maintaining metabolic homeostasis and insulin sensitization.

Depletion of FGF acts as a lateral inhibitory factor in lung branching morphogenesis in vitro.

Previous studies have shown that the interaction of positive and inhibitory signals plays a crucial role during lung branching morphogenesis. We found that in mesenchyme-free conditions, the lung epithelium exerted a lateral inhibitory effect on the neighbouring epithelium via depletion of fibroblast growth factor 1 (FGF1). Contrary to previous suggestions, bone morphogenetic protein 4 could not substitute for the inhibitory effect. Based on of this observation, we used a reaction-diffusion model of the substrate-depletion type to represent the initial phase of in vitro branching morphogenesis of lung epithelium, with depletion of FGF playing the role of lateral inhibitor. The model was able to account for the effects of the FGF1 concentration, extracellular matrix degradation and different subtypes of FGF on morphogenesis of the lung bud epithelia. These results suggest that the depletion of FGF may be a key regulatory component in initial phase of branching morphogenesis of the lung bud epithelium in vitro.

The PPARγ-FGF1 axis: an unexpected mediator of adipose tissue homeostasis.

Adipose tissue remodeling is a dynamic process during nutritional fluctuation that plays critical roles in metabolic homeostasis and insulin sensitivity. The process is highly regulated by many factors, including adipokines and cytokines that are locally released within fat pads. In a recent study published in Nature, Jonker and colleagues identified FGF1 as an important mediator that is selectively induced in fat cells by high-fat diet feeding and established the PPARγ-FGF1 axis as a critical pathway that regulates adipose tissue remodeling and ultimately systemic metabolic homeostasis.

Deficiency in inhibitory cortical interneurons associates with hyperactivity in fibroblast growth factor receptor 1 mutant mice.

BACKGROUND: Motor hyperactivity due to hyper-dopaminergic neurotransmission in the basal ganglia is well characterized; much less is known about the role of the neocortex in controlling motor behavior. METHODS: Locomotor behavior and motor, associative, and spatial learning were examined in mice with conditional null mutations of fibroblast growth factor receptor 1 (Fgfr1) restricted to telencephalic neural precursors (Fgfr1(f/f;hGfapCre)). Locomotor responses to a dopamine agonist (Amphetamine 2 mg/kg and Methylphenidate 10 mg/kg) and antagonists (SCH233390 .025 mg/kg and Haloperidol .2 mg/kg) were assessed. Stereological and morphological characterization of various monoaminergic, excitatory, and inhibitory neuronal subtypes was performed. RESULTS: Fgfr1(f/f;hGfapCre) mice have spontaneous locomotor hyperactivity characterized by longer bouts of locomotion and fewer resting points that is significantly reduced by the D1 and D2 receptor antagonists. No differences in dopamine transporter, tyrosine hydroxylase, or serotonin immunostaining were observed in Fgfr1(f/f;hGfapCre) mice. There was no change in cortical pyramidal neurons, but parvalbumin+, somatostatin+, and calbindin+ inhibitory interneurons were reduced in number in the cerebral cortex. The decrease in parvalbumin+ interneurons in cortex correlated with the extent of hyperactivity. CONCLUSIONS: Dysfunction in specific inhibitory cortical circuits might account for deficits in behavioral control, providing insights into the neurobiology of psychiatric disorders.

Role of fibroblast growth factor type 1 and 2 in carbon tetrachloride-induced hepatic injury and fibrogenesis.

Genomic ablation of hepatocyte-specific fibroblast growth factor receptor (FGFR)4 in mice revealed a role of FGF signaling in cholesterol and bile acid metabolism and hepatolobular restoration in response to injury without effect on liver development or hepatocyte proliferation. Although the potential role of all 23 FGF polypeptides in the liver is still unclear, the most widely studied prototypes, FGF1 and FGF2, are present and have been implicated in liver cell growth and function in vitro. To determine whether FGF1 and FGF2 play a role in response to injury and fibrosis, we examined the impact of both acute and chronic exposure to carbon tetrachloride (CCl(4)) in the livers of FGF1- and FGF2-deficient mice. After acute CCl(4) exposure, FGF1(-/-)FGF2(-/-) mice exhibited an accelerated release of serum alanine aminotransferase similar to FGFR4 deficiency, but no effect on overall hepatolobular restoration or bile acid metabolism. FGF1(-/-)FGF2(-/-) mice exhibited a normal increase in alpha-smooth muscle actin and desmin associated with activation and migration of hepatic stellate cells to damage, but a reduced level of hepatic stellate cell-derived matrix collagen alpha1(I) synthesis. Liver fibrosis resulting from chronic CCl(4) exposure was markedly decreased in the livers of FGF1/FGF2-deficient mice. These results suggest an agonist role for FGF1 and FGF2 in specifically insult-induced liver matrix deposition and hepatic fibrogenesis and a potential target for the prevention of hepatic fibrosis.