Pancreatic Sirtuin 3 deficiency enhances 5-hydroxytryptamine transcription and promotes hepatic steatosis in diet-induced obese mice
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AbstractPurpose of the study
Sirtuin 3 (Sirt3) is a mitochondrial protein deacetylase which regulates several metabolic pathways including glucose metabolism and fatty acid oxidation. In order to further study a more specific role of Sirt3 in pancreatic β cell, we generated a novel mice model of pancreatic β cell - specific Sirt3 knockout (Sirt3βKO) mice to study how SIRT3 regulates β cell function and its implications on glucose and lipid metabolism in high fat diet fed mice.

Methods
We generated pancreatic β cell specific Sirt3 knockout (Sirt3βKO) mice and their wild type littermates Sirt3βWT mice to compare the glycemic responses and β cell function using Ins1 (insulin)-promoter driven Cre-mediated deletion of floxed Sirt3 allele approach. Both Sirt3βKO and wild type mice were fed with high fat diet (HFD, 60% cal from fat) and standard diet (STD) for 36 weeks. Islets were isolated from these four groups for RNA sequencing (RNA-Seq) to explore the underlying mechanisms linking Sirt3 and beta cells function. The histological examination of liver tissues was conducted when the mice are sacrificed.

Summary of the results
We found that after feeding with HFD for 36 weeks, glucose tolerance and glucose induced insulin secretion were impaired in Sirt3βKO mice than WT mice. Histological analysis showed smaller hypertrophic change in islets from Sirt3βKO which correlated to less insulin production from these islets. Loss of SIRT3 also exacerbated the impaired insulin secretion induced by palmitic acid in isolated islet. Histological examination of the livers revealed that Sirt3βKO mice had more severe hepatic steatosis than WT mice upon HFD feeding. RNA-Seq on the islets collected from these Sirt3βKO mice and WT mice suggested that the 5-hydroxytryptamine (5-HT) synthesis pathway especially tryptophan hydroxylase 1 (Tph1) might be over-activated in Sirt3βKO mice islets and further enhanced by HFD feeding. 5-HT also facilitated the effect of palmitic acid to increase lipid deposition, and lipogenic gene expressions in hepatocytes.

Conclusions
Sirt3 may play a role in mediating pancreas-liver 5-HT signaling axis to regulate hepatic steatosis. Further studies are needed to examine whether increased 5-HT production in islet due to loss of SIRT3 acts as a paracrine signal to accelerate hepatic steatosis in the context of T2D.
All Author(s) ListMing X, Tian XY, Chung CK, Lee HM, Cao HY, Chan CN, Kong PS
Name of ConferenceEast meets west symposium 2019
Start Date of Conference28/09/2019
End Date of Conference29/09/2019
Place of ConferenceHong Kong
Country/Region of ConferenceHong Kong
Year2019
Month9
LanguagesEnglish-United States

Last updated on 2020-14-05 at 16:13