Retina and RPE-choroid – what fuels do they prefer in vivo?

Abstract

Purpose : The retina and RPE-choroid are proximal tissues in the posterior eye with symbiotic but vastly different functions. Emerging data suggests that these different functions are supported by distinct forms of metabolism, with the retina as a dominant consumer of glucose while RPE-choroid relies on a variety of alternate metabolic substrates. We tested the hypothesis that normally, energy metabolism in the retina is primarily supported by glucose while RPE-choroid metabolism is supported by a greater variety of fuels.

Methods : We installed jugular vein and carotid artery catheters into 2-5 month old C57BL/6J mice. We infused uniformly ¹³C labeled malate, succinate, glucose, lactate, palmitate, and glutamine through jugular catheters until the fuel was at steady-state labeling in circulation (2-4 hours). We then euthanized mice and determined ¹³C labeling patterns of downstream metabolites in plasma, retina, RPE-choroid, liver, and cerebellum using a combination of liquid- and gas-chromatography-linked mass spectrometry.

Results : Glucose was by far the most highly metabolized circulating substrate in both retina and RPE-choroid. In the retina glucose fuels ~80% of metabolism, but in contrast it supports only ~20% of metabolism in the RPE-choroid. Lactate, succinate, malate, glutamine, and palmitate each support TCA cycle activity in RPE-choroid to a lesser extent than glucose. In the retina metabolism of these alternate substrates is negligible. We also found that the RPE-choroid is unusually capable of oxidizing succinate, though normally this accounts for a relatively small proportion of total metabolic activity.

Conclusions : While it’s long been clear that glucose is metabolized rapidly by retinas, this is the first study to compare the relative proportion energy metabolism supported by glucose compared to other substrates. Retina tissue almost exclusively uses glucose. We have also supported the claim that the retina and RPE-choroid utilize vastly different forms of energy metabolism, as the RPE-choroid is partly supported by glucose but is also supported by several alternative fuels. Future studies will focus on identifying conditions that drive metabolite preferences, including how they are altered in disease states.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.