PURPOSE: The retinal pigment epithelium (RPE) performs life-long phagocytosis of lipid-rich photoreceptor outer segments and exchanges energy metabolites with photoreceptors to support retinal function. The metabolites of glucose and lipid metabolism are interconnected, but it is unclear how the specialized lipid metabolism of RPE and glucose metabolism are regulated. We have investigated this unique mechanism. METHODS: To identify factors involved in regulation of metabolism in RPE we compared and screened the human retinal pigment epithelial cell line, ARPE-19 under different conditions. Using the results of these experiments we selected the high-mobility group nucleosome-associated protein 1 (HMGN1) as a candidate and analyzed HMGN1 deleted ARPE-19 (HGMN1-/--ARPE-19) and Hmgn1 knock-out mice (Hmgn1-/- mice). RESULTS: HMGN1 was identified as being involved in energy metabolism via altered expression. HMGN1-/--ARPE-19 cells prefer fatty acid oxidation over glucose metabolism as an energy source. Hmgn1-/- mice had a lower lipid weight of epididymal fat mass and serum lipids than those of control on a standard diet and showed impaired glucose tolerance. The mice also showed retinal dysfunction, similar to that observed in aged control retina as measured by electroretinogram. However, a palmitate-rich diet, as well as RPE-specific HMGN1 re-expression mitigated retinal dysfunction. HMGN1 is specifically downregulated in the RPE/choroid with aging, which is reminiscent of age-related metabolic changes in RPE/choroid. CONCLUSIONS: HMGN1 is involved in energy metabolism and its altered expression modulates RPE-specific metabolic phenotypes.