Free fatty acids increase PGC-1α expression in isolated rat islets

PGC-1alpha mRNA and protein are elevated in islets from multiple animal models of diabetes. Overexpression of PGC-lalpha impairs glucose-stimulated insulin secretion (GSIS). However, it is not well known which metabolic events lead to upregulation of PGC-la in the P-cells under pathophysiological condition. In present study, we have investigated effects of chronic hyperlipidemia and hyperglycemia on PGC-la mRNA expression in isolated rat islets. Isolated rat islets are chronically incubated with 0, 0.2,and 0.4 mM oleic acid/palmitic acid (free fatty acids, FFA) or 5.5 and 25 mM glucose for 72 h. FFA dose-dependently increases PGC-lot mRNA expression level in isolated islets. FFA also increases PGC-1alpha expression in mouse eta-cell-derived betaTC3 cell line. In contrast, 25 mM glucose decreases expression level of PGC-la. Inhibition of PGC-lalpha by siRNA improves FFA-induced impairment of GSIS in islets. These data suggest that hyperlipidemia and hyperglycernia regulate PGC-lalpha expression in islets differently, and elevated PGC-la by FFA plays an important role in chronic hyperlipidemia-induced beta-cell dysfunction. (C) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.