Intestinal mTOR regulates GLP-1 production in mouse L cells

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• 作者：Geyang Xu ; Ziru Li ; Li Ding ; Hong Tang ; Song Guo ; Hongbin Liang…
• 关键词：Blood glucose ; Enteroendocrine L cells ; GLP ; 1 ; Intestine ; mTOR ; Neurogenin 3
• 刊名：Diabetologia
• 出版年：2015
• 出版时间：August 2015
• 年：2015
• 卷：58
• 期：8
• 页码：1887-1897
• 全文大小：1,739 KB
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• 作者单位：Geyang Xu (1)
  Ziru Li (2)
  Li Ding (2)
  Hong Tang (2)
  Song Guo (1)
  Hongbin Liang (1)
  Huadong Wang (3)
  Weizhen Zhang (2) (4)
  
  1. Department of Physiology, School of Medicine, Jinan University, Guangzhou, Guangdong, China
  2. Shenzhen University Diabetes Center, Shenzhen University Health Science Center, 3688 Nanhai Ave, Nanshan District, Shenzhen, Guangdong, 518060, China
  3. Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, Guangdong, China
  4. Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, USA
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Internal Medicine
  Metabolic Diseases
  Human Physiology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-0428

文摘

Aims/hypothesis Glucagon-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. Methods The effects of mTOR on GLP-1 production were examined in lean- or high-fat diet (HFD) induced diabetic C57/BL6, db/db, Neurog3-Tsc1 ??/em> 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. Results Fasting 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/interpretation mTOR may link energy supply with the production of GLP-1 in L cells.