title: Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice.
abstract: OBJECTIVE
  The mammalian target of rapamycin complex 1 (mTORC1)/p70 ribosomal S6 kinase (S6K)1 pathway is overactivated in obesity, leading to inhibition of phosphoinositide 3-kinase (PI3K)/Akt signalling and insulin resistance. However, chronic mTORC1 inhibition by rapamycin impairs glucose homeostasis because of robust induction of liver gluconeogenesis. Here, we compared the effect of rapamycin with that of the selective S6K1 inhibitor, PF-4708671, on glucose metabolism in vitro and in vivo.
  
  
  METHODS
  We used L6 myocytes and FAO hepatocytes to explore the effect of PF-4708671 on the regulation of glucose uptake, glucose production and insulin signalling. We also treated high-fat (HF)-fed obese mice for 7 days with PF-4708671 in comparison with rapamycin to assess glucose tolerance, insulin resistance and insulin signalling in vivo.
  
  
  RESULTS
  Chronic rapamycin treatment induced insulin resistance and impaired glucose metabolism in hepatic and muscle cells. Conversely, chronic S6K1 inhibition with PF-4708671 reduced glucose production in hepatocytes and enhanced glucose uptake in myocytes. Whereas rapamycin treatment inhibited Akt phosphorylation, PF-4708671 increased Akt phosphorylation in both cell lines. These opposite effects of the mTORC1 and S6K1 inhibitors were also observed in vivo. Indeed, while rapamycin treatment induced glucose intolerance and failed to improve Akt phosphorylation in liver and muscle of HF-fed mice, PF-4708671 treatment improved glucose tolerance and increased Akt phosphorylation in metabolic tissues of these obese mice.
  
  
  CONCLUSIONS
  Chronic S6K1 inhibition by PF-4708671 improves glucose homeostasis in obese mice through enhanced Akt activation in liver and muscle. Our results suggest that specific S6K1 blockade is a valid pharmacological approach to improve glucose disposal in obese diabetic individuals.
authors.affiliation: Department of Medicine, Quebec Heart and Lung Institute, Hôpital Laval, Pavillon Marguerite d'Youville, Room Y4308, 2705 Chemin Ste-Foy, Québec, Canada, G1V 4G5.
authors.forename: Michael
authors.initials: M
authors.lastname: Shum
authors.affiliation: Department of Medicine, Quebec Heart and Lung Institute, Hôpital Laval, Pavillon Marguerite d'Youville, Room Y4308, 2705 Chemin Ste-Foy, Québec, Canada, G1V 4G5.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Bellmann
authors.affiliation: Department of Medicine, Quebec Heart and Lung Institute, Hôpital Laval, Pavillon Marguerite d'Youville, Room Y4308, 2705 Chemin Ste-Foy, Québec, Canada, G1V 4G5.
authors.forename: Philippe
authors.initials: P
authors.lastname: St-Pierre
authors.affiliation: Department of Medicine, Quebec Heart and Lung Institute, Hôpital Laval, Pavillon Marguerite d'Youville, Room Y4308, 2705 Chemin Ste-Foy, Québec, Canada, G1V 4G5. andre.marette@criucpq.ulaval.ca.
authors.forename: André
authors.initials: A
authors.lastname: Marette
mesh_terms: D000818:Animals; D050260:Carbohydrate Metabolism / Q000187:drug effects; D002460:Cell Line; D005947:Glucose / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D008820:Mice, Obese; D046912:Multiprotein Complexes / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D007093:Imidazoles; D046912:Multiprotein Complexes; C552719:PF-4708671; D010879:Piperazines; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; C526901:Rps6kb1 protein, rat; D058570:TOR Serine-Threonine Kinases; D005947:Glucose; D020123:Sirolimus
keywords: Akt; Glucose tolerance; Glucose uptake; Hepatic glucose production; Insulin resistance; PF-4708671; Rapamycin; S6K1; Type 2 diabetes; mTORC1