title: Intestinal mTOR regulates GLP-1 production in mouse L cells.
abstract: OBJECTIVE
  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(-/-) 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
  mTOR may link energy supply with the production of GLP-1 in L cells.
authors.affiliation: Department of Physiology, School of Medicine, Jinan University, Guangzhou, Guangdong, China.
authors.forename: Geyang
authors.initials: G
authors.lastname: Xu
authors.forename: Ziru
authors.initials: Z
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.forename: Hong
authors.initials: H
authors.lastname: Tang
authors.forename: Song
authors.initials: S
authors.lastname: Guo
authors.forename: Hongbin
authors.initials: H
authors.lastname: Liang
authors.forename: Huadong
authors.initials: H
authors.lastname: Wang
authors.forename: Weizhen
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D059305:Diet, High-Fat; D015536:Down-Regulation; D019858:Enteroendocrine Cells / Q000187:drug effects / Q000378:metabolism*; D005215:Fasting / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D007930:Leucine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052336:Proglucagon / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D052336:Proglucagon; D052216:Glucagon-Like Peptide 1; D058570:TOR Serine-Threonine Kinases; D007930:Leucine; D020123:Sirolimus