Abstract

HIGHLIGHTSSirT1 induction and STAT3 inactivation promote hepatic glucose production.Deacetylation of STAT3 by SirT1 is required for PGC‐1&agr; activity on hepatic gluconeogenesis.Baicalin suppresses hepatic SirT1 induction by downregulating the levels of NAD+ in the fasting state.Preserving STAT3 acetylation and activation by baicalin contributes to restrain excessive hepatic glucose production. ABSTRACT Sirtuin 1 (SirT1) and signal transducer and activator of transcription 3 (STAT3) oppositely regulate hepatic gluconeogenic genes and the association remains to be elucidated. Baicalin is a natural flavonoid with beneficial effects on glucose and lipid metabolism. This study aims to investigate the effect of baicalin on hepatic gluconeogenesis with focus on the regulation of fatty acid mobilization and SirT1/STAT3 pathway. In HFD feeding or fasting state, hepatic gluconeogenesis and fatty acid oxidation induced SirT1 expression due to the increased nicotinamide adenine dinucleotide+ (NAD+) contents. Baicalin reduces endogenous glucose production via suppression of hepatic gluconeogenesis and decreased SirT1 induction via reducing NAD+ accumulation in an energy‐sensing way. Fasting increased SirT1 protein in STAT3 immunoprecipitation products and less in the liver of baicalin‐treated mice, indicating that baicalin blocked the binding of SirT1 to STAT3 and thus preserved STAT3 acetylation. SirT1 knockdown enhanced the protective effect of baicalin on pyruvate‐induced STAT3 phosphorylation and acetylation, these results further indicated that the regulation of STAT3 activity by baicalin was dependent on SirT1. Moreover, HFD feeding increased gene expression for PGC‐1&agr; in the liver, but the transcriptional regulation was inhibited by baicalin treatment.