Tissues with high metabolic rates often use lipids, as well as glucose, for energy, conferring a survival advantage during feast and famine1. Current dogma suggests that high-energy–consuming photoreceptors depend on glucose2,3. 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 photoreceptors4 and is expressed in other tissues with a high metabolic rate, facilitates the uptake of triglyceride-derived fatty acid5,6. In the retinas of Vldlr−/− mice with low fatty acid uptake6 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.
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This work was supported by the US National Institutes of Health (NIH) grants EY024864 (L.E.H.S.), EY017017 (L.E.H.S.), EY022275 (L.E.H.S.), P01 HD18655 (L.E.H.S.) and EY024963 (J.C.) and EY11254 (Friedlander), the Lowy Medical Research Institute (M. Friedlander, L.E.H.S. and M. Fruttiger), the European Commission FP7 project 305485 PREVENT-ROP (L.E.H.S.), a Burroughs Wellcome Fund Career Award for Medical Scientists (J.-S.J.), the Foundation Fighting Blindness (J.-S.J.), the Canadian Institute of Health Research (CIHR) grant 143077 (J.-S.J.), the Fonds de Recherche du Québec–Santé (FRQS) (J.-S.J.), the Canadian Child Health Clinician Scientist Program (J.-S.J.), a CIHR New Investigator Award (J.-S.J.), the Knights Templar Eye Foundation (Z.F.), the Bernadotte Foundation (Z.F.), the Canada Research chair and CIHR grant 221478 (P.S.), the Boston Children's Hospital Ophthalmology Foundation (J.C.), a Boston Children's Hospital Faculty Career Development Award (J.C.), the Bright Focus Foundation (J.C.) and the Massachussetts Lions Eye Research Fund, Inc. (J.C.). We thank M. Puder and P. Nandivada (Harvard Medical School, Boston Children's Hospital) for sharing the Ffar1−/− mice; M. Al-Ubaidi (University of Oklahoma) for sharing the 661W photoreceptor cells; Z. Lin and W.T. Pu (Harvard Medical School, Boston Children's Hospital) for sharing a modified CAG-GFP-miR30 construct; and C. Cepko (Harvard Medical School) and T. Li (National Eye Institute) for providing the pAAV-RK-GFP vector.
The authors declare no competing financial interests.
Supplementary Figures 1–10 and Supplementary Tables 1–2 (PDF 10547 kb)
Video of pseudo-colored mitochondria in WT photoreceptors by 3D reconstruction of scanning electron microscopy (MOV 4894 kb)
Video of pseudo-colored mitochondria in Vldlr−/− photoreceptors by 3D reconstruction of scanning electron microscopy. A vascular lesion (center) is pseudocoloured in green. (MOV 15200 kb)
[18F]FDG microPET / CT scan comparing glucose uptake simultaneously in WT (left), Vldlr−/− (middle left), Vldlr−/− /Ffar1−/− (middle right) and Ffar1−/− mice (right) (MPG 982 kb)
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Joyal, JS., Sun, Y., Gantner, M. et al. Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1. Nat Med 22, 439–445 (2016). https://doi.org/10.1038/nm.4059
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