Pancreatic Sirtuin 3 deficiency promotes hepatic steatosis by enhancing 5-hydroxytryptamine synthesis in diet-induced Obese mice
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
Sirtuin 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.
Date Issued
2020-10-21
Date Acceptance
2020-10-12
Citation
Diabetes, 2020, 70 (1), pp.119-131
ISSN
0012-1797
Publisher
American Diabetes Association
Start Page
119
End Page
131
Journal / Book Title
Diabetes
Volume
70
Issue
1
Copyright Statement
© 2020 by the American Diabetes Association https://www.diabetesjournals.org/content/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/content/license.
Sponsor
Diabetes UK
Wellcome Trust
Medical Research Council (MRC)
Diabetes UK
Diabetes UK
Diabetes UK
Diabetes UK
Medical Research Council (MRC)
The Leverhulme Trust
Juvenile Diabetes Research Foundation International
Medical Research Council
Rosetrees Trust
Institut De Recherches Servier
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/33087457
PII: db20-0339
Grant Number
15/0005374
212625/Z/18/Z
R15019
12/0004535
18/0005934
16/0005485
16/0005485
MR/J013293/2
RF/4/RFG/2009/0493
3-2009-665
MR/R022259/1 (2018 – 2023)
M529
115881
Subjects
Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
INSULIN-RESISTANCE
BETA-CELLS
GLUCAGON-SECRETION
LIVER-DISEASE
SEROTONIN
MOUSE
DEACETYLASE
TRYPTOPHAN
RELEASE
HOMOLOG
Endocrinology & Metabolism
11 Medical and Health Sciences
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2020-10-21