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Intestinal mTOR regulates GLP-1 production in mouse L cells

Authors
  • Xu, Geyang1
  • Li, Ziru2
  • Ding, Li2
  • Tang, Hong2
  • Guo, Song1
  • Liang, Hongbin1
  • Wang, Huadong3
  • Zhang, Weizhen2, 4
  • 1 Jinan University, Department of Physiology, School of Medicine, Guangzhou, Guangdong, China , Guangzhou (China)
  • 2 Shenzhen University Diabetes Center, Shenzhen University Health Science Center, 3688 Nanhai Ave, Nanshan District, Shenzhen, Guangdong, 518060, China , Shenzhen (China)
  • 3 Jinan University, Department of Pathophysiology, School of Medicine, Guangzhou, Guangdong, China , Guangzhou (China)
  • 4 University of Michigan Medical Center, Department of Surgery, Ann Arbor, MI, USA , Ann Arbor (United States)
Type
Published Article
Journal
Diabetologia
Publisher
Springer-Verlag
Publication Date
Jun 03, 2015
Volume
58
Issue
8
Pages
1887–1897
Identifiers
DOI: 10.1007/s00125-015-3632-6
Source
Springer Nature
Keywords
License
Yellow

Abstract

Aims/hypothesisGlucagon-like peptide (GLP-1), an intestinal incretin produced in L cells through proglucagon processing, is released in response to meal intake. The intracellular mechanism by which L cells sense the organism energy level to coordinate the production of GLP-1 remains unclear. Mechanistic target of rapamycin (mTOR) is an intracellular fuel sensor critical for energy homeostasis. In this study, we investigated whether intestinal mTOR regulates GLP-1 production in L cells.MethodsThe effects of mTOR on GLP-1 production were examined in lean- or high-fat diet (HFD) induced diabetic C57/BL6, db/db, Neurog3-Tsc1−/− mice, and STC-1 cells. GLP-1 expression was investigated by real-time PCR and western blotting. Plasma GLP-1 and insulin were detected by enzyme immunoassay and radioimmunoassay, respectively.ResultsFasting downregulated mTOR activity, which was associated with a decrement of intestinal proglucagon and circulating GLP-1. Upon re-feeding, these alterations returned to the levels of fed animals. In HFD induced diabetic mice, ileal mTOR signalling, proglucagon and circulating GLP-1 were significantly decreased. Inhibition of mTOR signalling by rapamycin decreased levels of intestinal and plasma GLP-1 in both normal and diabetic mice. Activation of the intestinal mTOR signalling by l-leucine or Tsc1 gene deletion increased levels of intestinal proglucagon and plasma GLP-1. Overexpression of mTOR stimulated proglucagon promoter activity and GLP-1 production, whereas inhibition of mTOR activity by overexpression of tuberous sclerosis 1 (TSC1) or TSC2 decreased proglucagon promoter activity and GLP-1 production in STC-1 cells.Conclusions/interpretationmTOR may link energy supply with the production of GLP-1 in L cells.

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