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Postnatal hyperglycemia contributes to Phase I ROP by delaying retinal vascularization. In mouse neonates with hyperglycemia-associated Phase I retinopathy, dietary \u03c9-3 (vs. \u03c9-6 LCPUFA) supplementation promoted retinal vessel development. However, \u03c9-6 (vs. \u03c9-3 LCPUFA) was also developmentally essential, promoting neuronal growth and metabolism as suggested by a strong metabolic shift in almost all types of retinal neuronal and glial cells identified with single-cell transcriptomics. Loss of adiponectin (APN) in mice (mimicking the low APN levels in Phase I ROP) decreased LCPUFA levels (including \u03c9-3 and \u03c9-6) in retinas under normoglycemic and hyperglycemic conditions. \u03c9-3 (vs. \u03c9-6) LCPUFA activated the APN pathway by increasing the circulating APN levels and inducing expression of the retinal APN receptor. Our findings suggested that both \u03c9-3 and \u03c9-6 LCPUFA are crucial in protecting against retinal neurovascular dysfunction in a Phase I ROP model; adequate \u03c9-6 LCPUFA levels must be maintained in addition to \u03c9-3 supplementation to prevent retinopathy. Activation of the APN pathway may further enhance the \u03c9-3 and \u03c9-6 LCPUFA\u2019s protection against ROP.<\/jats:p>","DOI":"10.3390\/nu14071333","type":"journal-article","created":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T22:08:06Z","timestamp":1648073286000},"page":"1333","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Omega-3\/Omega-6 Long-Chain Fatty Acid Imbalance in Phase I Retinopathy of Prematurity"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8182-2983","authenticated-orcid":false,"given":"Zhongjie","family":"Fu","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3568-4265","authenticated-orcid":false,"given":"Wenjun","family":"Yan","sequence":"additional","affiliation":[{"name":"Center for Brain Science, Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuck T.","family":"Chen","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3631-0783","authenticated-orcid":false,"given":"Anders K.","family":"Nilsson","sequence":"additional","affiliation":[{"name":"Section for Ophthalmology, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 412 96 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Bull","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Allen","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minji","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Paul","family":"SanGiovanni","sequence":"additional","affiliation":[{"name":"BIO5 Institute, Department of Nutritional Sciences, The University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James D.","family":"Akula","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saswata","family":"Talukdar","sequence":"additional","affiliation":[{"name":"Cardiometabolic Diseases, Merck Research Laboratories, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9259-1244","authenticated-orcid":false,"given":"Ann","family":"Hellstr\u00f6m","sequence":"additional","affiliation":[{"name":"Section for Ophthalmology, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 412 96 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lois E. 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