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

PGC-1α mRNA and protein are elevated in islets from multiple animal models of diabetes. Overexpression of PGC-1α impairs glucose-stimulated insulin secretion (GSIS). However, it is not well known which metabolic events lead to upregulation of PGC-1α in the β-cells under pathophysiological condition. In present study, we have investigated effects of chronic hyperlipidemia and hyperglycemia on PGC-1α 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-1α mRNA expression level in isolated islets. FFA also increases PGC-1α expression in mouse β-cell-derived βTC3 cell line. In contrast, 25 mM glucose decreases expression level of PGC-1α. Inhibition of PGC-1α by siRNA improves FFA-induced impairment of GSIS in islets. These data suggest that hyperlipidemia and hyperglycemia regulate PGC-1α expression in islets differently, and elevated PGC-1α by FFA plays an important role in chronic hyperlipidemia-induced β-cell dysfunction.