PGC-1 coactivators in @b-cells regulate lipid metabolism and are essential for insulin secretion coupled to fatty acids

摘要

Objectives: Peroxisome proliferator-activated receptor @c coactivator 1 (PPARGCA1, PGC-1) transcriptional coactivators control gene programs important for nutrient metabolism. Islets of type 2 diabetic subjects have reduced PGC-1@a expression and this is associated with decreased insulin secretion, yet little is known about why this occurs or what role it plays in the development of diabetes. Our goal was to delineate the role and importance of PGC-1 proteins to @b-cell function and energy homeostasis. Methods: We investigated how nutrient signals regulate coactivator expression in islets and the metabolic consequences of reduced PGC-1@a and PGC-1@b in primary and cultured @b-cells. Mice with inducible @b-cell specific double knockout of Pgc-1@a/Pgc-1@b (@bPgc-1 KO) were created to determine the physiological impact of reduced Pgc1 expression on glucose homeostasis. Results: Pgc-1@a and Pgc-1@b expression was increased in primary mouse and human islets by acute glucose and palmitate exposure. Surprisingly, PGC-1 proteins were dispensable for the maintenance of mitochondrial mass, gene expression, and oxygen consumption in response to glucose in adult @b-cells. However, islets and mice with an inducible, @b-cell-specific PGC-1 knockout had decreased insulin secretion due in large part to loss of the potentiating effect of fatty acids. Consistent with an essential role for PGC-1 in lipid metabolism, @b-cells with reduced PGC-1s accumulated acyl-glycerols and PGC-1s controlled expression of key enzymes in lipolysis and the glycerolipid/free fatty acid cycle. Conclusions: These data highlight the importance of PGC-1s in coupling @b-cell lipid metabolism to promote efficient insulin secretion.