Mechanisms responsible for the pathogenesis of diabetic retinal disease remain incompletely understood, but likely involve multiple cellular targets, including photoreceptors. Evidence suggests that dysregulated de novo lipogenesis in photoreceptors is a critical early target of diabetes. Following on this observation, the present study aimed to determine whether two interventions shown to improve diabetic retinopathy in mice – pharmacologic visual cycle inhibition and prolonged dark adaptation – reduce photoreceptor anabolic lipid metabolism. Elevated retinal lipid biosynthetic signaling was observed in two mouse models of diabetes, with both models showing reduced retinal adenosine monophosphate-activated kinase (AMPK) signaling, elevated acetyl co-A carboxylase (ACC) signaling, and increased activity of fatty acid synthase (FAS), which promotes lipotoxicity in photoreceptors. Whereas retinal AMPK-ACC axis signaling was dependent on systemic glucose fluctuations in healthy animals, mice with diabetes lacked such regulation. Visual cycle inhibition and prolonged dark adaptation reversed abnormal retinal AMPK-ACC signaling in mice with diabetes. While visual cycle inhibition reduced the severity of diabetic retinopathy in control mice, as assessed by retinal capillary atrophy, this intervention was ineffective in FAS gain-of-function mice. These results suggest that early diabetic retinopathy is characterized by glucose-driven elevations in retinal lipid biosynthetic activity, and that two interventions known to increase photoreceptor glucose demands alleviate disease by reversing these signals.
Copyright © 2023. Published by Elsevier Inc.