TY - JOUR
T1 - Phagocytosis in the retina promotes local insulin production in the eye
AU - Iker Etchegaray, J.
AU - Kelley, Shannon
AU - Penberthy, Kristen
AU - Karvelyte, Laura
AU - Nagasaka, Yosuke
AU - Gasperino, Sofia
AU - Paul, Soumen
AU - Seshadri, Vikram
AU - Raymond, Michael
AU - Marco, Ana Royo
AU - Pinney, Jonathan
AU - Stremska, Marta
AU - Barron, Brady
AU - Lucas, Christopher
AU - Wase, Nishikant
AU - Fan, Yong
AU - Unanue, Emil
AU - Kundu, Bijoy
AU - Burstyn-Cohen, Tal
AU - Perry, Justin
AU - Ambati, Jayakrishna
AU - Ravichandran, Kodi S.
N1 - Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2023/2
Y1 - 2023/2
N2 - The retina is highly metabolically active, relying on glucose uptake and aerobic glycolysis. Situated in close contact to photoreceptors, a key function of cells in the retinal pigment epithelium (RPE) is phagocytosis of damaged photoreceptor outer segments (POS). Here we identify RPE as a local source of insulin in the eye that is stimulated by POS phagocytosis. We show that Ins2 messenger RNA and insulin protein are produced by RPE cells and that this production correlates with RPE phagocytosis of POS. Genetic deletion of phagocytic receptors (‘loss of function’) reduces Ins2, whereas increasing the levels of the phagocytic receptor MerTK (‘gain of function’) increases Ins2 production in male mice. Contrary to pancreas-derived systemic insulin, RPE-derived local insulin is stimulated during starvation, which also increases RPE phagocytosis. Global or RPE-specific Ins2 gene deletion decreases retinal glucose uptake in starved male mice, dysregulates retinal physiology, causes defects in phototransduction and exacerbates photoreceptor loss in a mouse model of retinitis pigmentosa. Collectively, these data identify RPE cells as a phagocytosis-induced local source of insulin in the retina, with the potential to influence retinal physiology and disease.
AB - The retina is highly metabolically active, relying on glucose uptake and aerobic glycolysis. Situated in close contact to photoreceptors, a key function of cells in the retinal pigment epithelium (RPE) is phagocytosis of damaged photoreceptor outer segments (POS). Here we identify RPE as a local source of insulin in the eye that is stimulated by POS phagocytosis. We show that Ins2 messenger RNA and insulin protein are produced by RPE cells and that this production correlates with RPE phagocytosis of POS. Genetic deletion of phagocytic receptors (‘loss of function’) reduces Ins2, whereas increasing the levels of the phagocytic receptor MerTK (‘gain of function’) increases Ins2 production in male mice. Contrary to pancreas-derived systemic insulin, RPE-derived local insulin is stimulated during starvation, which also increases RPE phagocytosis. Global or RPE-specific Ins2 gene deletion decreases retinal glucose uptake in starved male mice, dysregulates retinal physiology, causes defects in phototransduction and exacerbates photoreceptor loss in a mouse model of retinitis pigmentosa. Collectively, these data identify RPE cells as a phagocytosis-induced local source of insulin in the retina, with the potential to influence retinal physiology and disease.
UR - http://www.scopus.com/inward/record.url?scp=85147294422&partnerID=8YFLogxK
U2 - 10.1038/s42255-022-00728-0
DO - 10.1038/s42255-022-00728-0
M3 - Article
C2 - 36732622
AN - SCOPUS:85147294422
SN - 2522-5812
VL - 5
SP - 207
EP - 218
JO - Nature Metabolism
JF - Nature Metabolism
IS - 2
ER -