title: Ghrelin contributes to derangements of glucose metabolism induced by rapamycin in mice.
abstract: OBJECTIVE
  Rapamycin impairs glucose tolerance and insulin sensitivity. Our previous study demonstrated that rapamycin significantly increases the production of gastric ghrelin, which is critical in the regulation of glucose metabolism. Here, we investigated whether ghrelin contributes to derangements of glucose metabolism induced by rapamycin.
  
  
  METHODS
  The effects of rapamycin on glucose metabolism were examined in mice receiving ghrelin receptor antagonist or with Ghsr1a gene knockout. Changes in GLUT4, c-Jun N-terminal kinase (JNK) and phosphorylated ribosomal protein S6 (pS6) were investigated by immunofluorescent staining or western blotting. Related hormones were detected by radioimmunoassay kits.
  
  
  RESULTS
  Rapamycin impaired glucose metabolism and insulin sensitivity not only in normal C57BL/6J mice but also in both obese mice induced by a high fat diet and db/db mice. This was accompanied by elevation of plasma acylated ghrelin. Rapamycin significantly increased the levels of plasma acylated ghrelin in normal C57BL/6J mice, high-fat-diet-induced obese mice and db/db mice. Elevation in plasma acylated ghrelin and derangements of glucose metabolism upon administration of rapamycin were significantly correlated. The deterioration in glucose homeostasis induced by rapamycin was blocked by D: -Lys3-GHRP-6, a ghrelin receptor antagonist, or by deletion of the Ghsr1a gene. Ghrelin receptor antagonism and Ghsr1a knockout blocked the upregulation of JNK activity and downregulation of GLUT4 levels and translocation in the gastrocnemius muscle induced by rapamycin.
  
  
  CONCLUSIONS
  The current study demonstrates that ghrelin contributes to derangements of glucose metabolism induced by rapamycin via altering the content and translocation of GLUT4 in muscles.
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, No 38, Xueyuan Rd, Haidian District, Beijing 100191, People's Republic of China.
authors.forename: G
authors.initials: G
authors.lastname: Xu
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.forename: H
authors.initials: H
authors.lastname: Tang
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.forename: X
authors.initials: X
authors.lastname: Xiang
authors.forename: L
authors.initials: L
authors.lastname: Ding
authors.forename: L
authors.initials: L
authors.lastname: Ma
authors.forename: F
authors.initials: F
authors.lastname: Yuan
authors.forename: J
authors.initials: J
authors.lastname: Fei
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.forename: N
authors.initials: N
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Guan
authors.forename: C
authors.initials: C
authors.lastname: Tang
authors.forename: M
authors.initials: M
authors.lastname: Mulholland
authors.forename: W
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D054439:Ghrelin / Q000097:blood / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009842:Oligopeptides / Q000494:pharmacology; D011863:Radioimmunoassay; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*
chemical_list: C520836:GHRP-6, Lys(3)-; D054439:Ghrelin; D051275:Glucose Transporter Type 4; D009842:Oligopeptides; D054440:Receptors, Ghrelin; D038601:Ribosomal Protein S6; D048031:JNK Mitogen-Activated Protein Kinases; D005947:Glucose; D020123:Sirolimus