Fibroblast Growth Factor 21 Protects Photoreceptor Function in Type 1 Diabetic Mice

Abstract

Retinal neuronal abnormalities occur before vascular changes in diabetic retinopathy. Accumulating experimental evidence suggests that neurons control vascular pathology in diabetic and other neovascular retinal diseases. Therefore, normalizing neuronal activity in diabetes may prevent vascular pathology. We investigated whether fibroblast growth factor 21 (FGF21) prevented retinal neuronal dysfunction in insulin-deficient diabetic mice. We found that in diabetic neural retina, photoreceptor rather than inner retinal function was most affected and administration of the long-acting FGF21 analog PF-05231023 restored the retinal neuronal functional deficits detected by electroretinography. PF-05231023 administration protected against diabetes-induced disorganization of photoreceptor segments seen in retinal cross section with immunohistochemistry and attenuated the reduction in the thickness of photoreceptor segments measured by optical coherence tomography. PF-05231023, independent of its downstream metabolic modulator adiponectin, reduced inflammatory marker interleukin-1β (IL-1β) mRNA levels. PF-05231023 activated the AKT-nuclear factor erythroid 2-related factor 2 pathway and reduced IL-1β expression in stressed photoreceptors. PF-05231023 administration did not change retinal expression of vascular endothelial growth factor A, suggesting a novel therapeutic approach for the prevention of early diabetic retinopathy by protecting photoreceptor function in diabetes.

Long-Acting FGF21 Inhibits Retinal Vascular Leakage in In Vivo and In Vitro Models

“…In addition to our current finding that FGF21 inhibits vascular leakage, we have previously reported that FGF21 also inhibits pathological choroidal and retinal neovascularization [16], as well as protects against neuronal degeneration in T1D mice [17]. Taken together, we propose that FGF21 could be a therapeutic target for preventing macular edema and proliferative retinopathies.…”

“…FGF21 reduces body weight and improves the lipid profile in patients with Type 2 diabetes, as well as in primate and rodent models of Type 2 diabetes [14,15]. We have reported that long-acting FGF21, with a longer half-life than native FGF21, prevents pathological neovascularization in the retina and choroid in several murine models, and also protects photoreceptor function in diabetic mice [16,17]. However, the impact of FGF21 on retinal vascular leakage has not yet been explored.…”

Heparin‐poloxamer hydrogel‐encapsulated rhFGF21 enhances wound healing in diabetic mice

“…However, to the best of our knowledge, no research has shown that FGF21 can repair skin wounds. Because FGF21 has anti-inflammatory abilities, regulates metabolism, and promotes the repair of some injuries (20,21), we hypothesized that FGF21 may enhance skin wound healing in diabetic mice. However, growth factors rapidly degrade in vivo, and therefore, we needed a suitable delivery vehicle to maintain the biologic activity and bioavailability of growth factors, transport them safely to the wound, and control their release.…”

“…Therefore, FGF21 can be safely used in clinical applications (19). FGF21 has been reported to improve photoreceptor function by reducing photoreceptor oxidative stress and inflammation through metabolism regulation (20). Moreover, FGF21 can improve cardiac function in T2DMinduced cardiomyopathy (21) by regulating metabolic disruption.…”

Dyslipidemia in retinal metabolic disorders

“…In diabetic mice with insulin deficiency, FGF21 enhances retinal antioxidant defense systems, reduces pro‐inflammatory cytokines, restores disorganized cone photoreceptor segments, and improves retinal function (Fu et al , ). FGF21 also regulates adiponectin (APN) production and secretion, and APN is key in mediating FGF21 modulation of glucose and lipid metabolism in mice (Holland et al , ; Lin et al , ).…”