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Pancreatic Sirtuin 3 deficiency promotes hepatic steatosis by enhancing 5-hydroxytryptamine synthesis in diet-induced obese mice
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posted on 2020-10-21, 18:15 authored by Ada AdminAda Admin, Xing Ming, Arthur C.K. Chung, Dandan Mao, Huanyi Cao, Baoqi Fan, Willy K.K. Wong, Chin Chung Ho, Heung Man Lee, Kristina Schoonjans, Johan Auwerx, Guy A. Rutter, Juliana C.N. Chan, Xiao Yu Tian, Alice P.S. KongSirtuin
3 (SIRT3) is a protein deacetylase regulating beta cell function through
inhibiting oxidative stress in obese and diabetic mice, but the detailed
mechanism and potential effect of beta cell specific SIRT3 on metabolic
homeostasis, and its potential effect on other metabolic organs are unknown. We
found glucose tolerance and glucose stimulated insulin secretion (GSIS) were
impaired in high fat diet (HFD)-fed beta cell selective Sirt3 knockout (Sirt3f/f;Cre/+) mice. In addition, Sirt3f/f;Cre/+
mice had more severe hepatic steatosis than Sirt3f/f mice upon HFD feeding. RNA
sequencing (RNA-Seq) of islets suggested that Sirt3 deficiency over-activated
5-hydroxytryptamine (5-HT) synthesis as evidenced by up-regulation of tryptophan
hydroxylase 1 (TPH1). 5-HT concentration was increased in both islets and serum
of Sirt3f/f;Cre/+ mice. 5-HT also facilitated the effect of
palmitate to increase lipid deposition. Treatment with TPH1 inhibitor
ameliorated hepatic steatosis and reduced weight gain in HFD-fed Sirt3f/f;Cre/+ mice. These data suggested that under HFD
feeding, SIRT3 deficiency in beta cells not only regulates insulin secretion
but also modulates hepatic lipid metabolism via the release of 5-HT.