TY - JOUR
T1 - Increasing Energetic Demands on Photoreceptors in Diabetes Corrects Retinal Lipid Dysmetabolism and Reduces Subsequent Microvascular Damage
AU - Zhang, Sheng
AU - Wei, Xiaochao
AU - Bowers, Megan
AU - Jessberger, Sebastian
AU - Golczak, Marcin
AU - Semenkovich, Clay F.
AU - Rajagopal, Rithwick
N1 - Publisher Copyright:
© 2023 American Society for Investigative Pathology
PY - 2023/12
Y1 - 2023/12
N2 - Mechanisms responsible for the pathogenesis of diabetic retinal disease remain incompletely understood, but they 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 AMP-activated kinase (AMPK) signaling, elevated acetyl CoA carboxylase (ACC) signaling, and increased activity of fatty acid synthase, which promotes lipotoxicity in photoreceptors. Although 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. Although visual cycle inhibition reduced the severity of diabetic retinopathy in control mice, as assessed by retinal capillary atrophy, this intervention was ineffective in fatty acid synthase 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.
AB - Mechanisms responsible for the pathogenesis of diabetic retinal disease remain incompletely understood, but they 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 AMP-activated kinase (AMPK) signaling, elevated acetyl CoA carboxylase (ACC) signaling, and increased activity of fatty acid synthase, which promotes lipotoxicity in photoreceptors. Although 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. Although visual cycle inhibition reduced the severity of diabetic retinopathy in control mice, as assessed by retinal capillary atrophy, this intervention was ineffective in fatty acid synthase 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.
UR - http://www.scopus.com/inward/record.url?scp=85177175711&partnerID=8YFLogxK
U2 - 10.1016/j.ajpath.2023.09.004
DO - 10.1016/j.ajpath.2023.09.004
M3 - Article
C2 - 37741454
AN - SCOPUS:85177175711
SN - 0002-9440
VL - 193
SP - 2144
EP - 2155
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 12
ER -