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Retinal neovascularization, as occurs in age-related macular degeneration, may result from an increase in VEGFA levels due to dysregulated lipid and glucose metabolism within photoreceptors. Tissues with high metabolic rates often use lipids, as well as glucose, for energy, conferring a survival advantage during feast and famine 1 . Current dogma suggests that high-energy–consuming photoreceptors depend on glucose 2 , 3 . Here we show that the retina also uses fatty acid β-oxidation for energy. Moreover, we identify a lipid sensor, free fatty acid receptor 1 (Ffar1), that curbs glucose uptake when fatty acids are available. Very-low-density lipoprotein receptor (Vldlr), which is present in photoreceptors 4 and is expressed in other tissues with a high metabolic rate, facilitates the uptake of triglyceride-derived fatty acid 5 , 6 . In the retinas of Vldlr −/− mice with low fatty acid uptake 6 but high circulating lipid levels, we found that Ffar1 suppresses expression of the glucose transporter Glut1. Impaired glucose entry into photoreceptors results in a dual (lipid and glucose) fuel shortage and a reduction in the levels of the Krebs cycle intermediate α-ketoglutarate (α-KG). Low α-KG levels promotes stabilization of hypoxia-induced factor 1a (Hif1a) and secretion of vascular endothelial growth factor A (Vegfa) by starved Vldlr −/− photoreceptors, leading to neovascularization. The aberrant vessels in the Vldlr −/− retinas, which invade normally avascular photoreceptors, are reminiscent of the vascular defects in retinal angiomatous proliferation, a subset of neovascular age-related macular degeneration (AMD) 7 , which is associated with high vitreous VEGFA levels in humans. Dysregulated lipid and glucose photoreceptor energy metabolism may therefore be a driving force in macular telangiectasia, neovascular AMD and other retinal diseases.

The mouse retinal vasculature provides a powerful model system for studying development and pathologies of the vasculature. Because it forms as a two-dimensional flat plexus, it is easily imaged in its entirety in whole-mount retinal preparations. In order to study molecular signaling mechanisms, it is useful to visualize the expression of specific genes in the entire vascular plexus and retina. However, in situ hybridization on whole-mount retinal preparations is problematic because isolated retinas have a tendency to curl up during hybridization and are difficult to stain. Here we provide a detailed protocol that overcomes these difficulties and visualizes the mRNA distribution of one or two genes in the context of the counterstained retinal vasculature. The protocol takes 3–4 d for single-probe stains, with an additional 2 d for immunohistochemistry co-labeling. In situ hybridization with two probes adds a further 3 d.

Nat. Med.; doi: 10.1038/nm.4059; corrected 24 March 2016 In the version of this article initially published online, there were two errors. There was a typographical error in the text, which should have stated that the 'dark current' is an electrochemical gradient required for photon-induced polarization (rather than depolarization, as incorrectly stated).

Retinal neovascularization, as occurs in age-related macular degeneration, may result from an increase in VEGFA levels due to dysregulated lipid and glucose metabolism within photoreceptors.