Retinopathy of prematurity (ROP) affects ~16,000 premature infants per year in the US. At preterm birth, loss of ω3 long-chain polyunsaturated fatty acid (LCPUFA), normally provided by the maternal/placental interface prominently contributes to initiation and progression of ROP. The link between ω3LCPUFA and glucose metabolism has not been explored although in human ROP, hyperglycemia during phase I (vessel loss or suppression of vessel development) is very strongly associated with retinopathy progression. In mouse pups we found that hyperglycemia delayed retinal vascular development (phase I ROP) which was greatly attenuated with dietary ω3LCPUFAs. To define the link between ω3LCPUFA and glucose control we looked to an important adipocyte-derived hormone and metabolic regulator, adiponectin (APN). In premature infants, low ω-3LCPUFA, low serum APN, and hyperglycemia are all correlated with development of ROP. We will explore ω3LCPUFA effects on hyperglycemic exacerbation of early vessel loss in ROP and the role of hormones in ω3LCPUFA protection against hyperglycemic retinopathy. ω3LCPUFA regulates lipid/glucose metabolism to prevent hyperglycemia-induced ROP through APN In hyperglycemic mice in phase I ROP (vessel growth suppression) we will: i) ω3LCPUFA protects against hyperglycemia-induced suppression of retinal development (phase I ROP); ii) determine retinal and vessel glucose/lipid metabolic regulation with ω3LCPUFA preservation of vessels during hyperglycemia, and iii) determine if APN mediates ω3LCPUFA vascular and neuronal retina protection in neonatal hyperglycemia. SUMMARY: These studies will determine ω3LCPUFA metabolic control (through lipid associated hormones) of hyperglycemia, which increases ROP risk. Hormonal modulation is likely to lead to new preventive approaches and treatment options for ROP and has therapeutic implications for many other diseases.