ERRgamma and Pancreatic beta-cell function

Estrogen-related receptor ? (ERR?) signaling increases during the neonatal to adult transition in pancreatic islet ß-cells. We show that ß-cell-specific ERR?-deficient (ßERR?KO) mice exhibit glucose intolerance with reduced glucose-stimulated insulin secretion (GSIS) and ßERR?KO islets have defective GSIS function accompanied by changes in genes that regulate ATP biosynthesis, oxidative phosphorylation, and the electron transport chain. ERR? overexpression enhances genes involved in mitochondrial metabolism, resulting in transformation of ß-like-cells into metabolically functional ß-cells that can ameliorate STZ-induced hyperglycemia in NOD-SCID mice. These results suggest that ERR? signaling is essential for the metabolic maturation of ß-like-cells and thus represents a novel therapeutic target in the treatment of diabetes.

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Yoshihara E, Wei Z, Lin CS, Fang S, Ahmadian M, Kida Y, Tseng T, Dai Y, Yu RT, Liddle C, Atkins AR, Downes M, Evans RM