Pancreatic Sirtuin 3 Deficiency Promotes Hepatic Steatosis by Enhancing 5-Hydroxytryptamine Synthesis in Mice With Diet-Induced Obesity

Sirtuin 3 (SIRT3) is a protein deacetylase regulating β-cell function through inhibiting oxidative stress in obese and diabetic mice, but the detailed mechanism and potential effect of β-cell–specific SIRT3 on metabolic homeosta-sis, and its potential effect on other metabolic organs, are unknown. We found that glucose tolerance and glucose-stimulated insulin secretion were impaired in high-fat diet (HFD)-fed β-cell–selective Sirt3 knockout (Sirt3) mice. In addition, Sirt3 mice had more severe hepatic steatosis than Sirt3 mice upon HFD feeding. RNA sequencing of islets suggested that Sirt3 deficiency overactivated 5-hydroxytryptamine (5-HT) synthesis as evidenced by upregulation of trypto-phan hydroxylase 1 (TPH1). 5-HT concentration was increased in both islets and serum of Sirt3 mice. 5-HT also facilitated the effect of palmitate to increase lipid deposition. Treatment with TPH1 inhibitor ame-liorated hepatic steatosis and reduced weight gain in HFD-fed Sirt3 mice. These data suggested that under HFD feeding, SIRT3 deficiency in β-cells not only regulates insulin secretion but also modulates hepatic lipid metabolism via the release of 5-HT.