title: Amino Acids Attenuate Insulin Action on Gluconeogenesis and Promote Fatty Acid Biosynthesis via mTORC1 Signaling Pathway in trout Hepatocytes.
abstract: OBJECTIVE
  Carnivores exhibit poor utilization of dietary carbohydrates and glucose intolerant phenotypes, yet it remains unclear what are the causal factors and underlying mechanisms. We aimed to evaluate excessive amino acids (AAs)-induced effects on insulin signaling, fatty acid biosynthesis and glucose metabolism in rainbow trout and determine the potential involvement of mTORC1 and p38 MAPK pathway.
  
  
  METHODS
  We stimulated trout primary hepatocytes with different AA levels and employed acute administration of rapamycin to inhibit mTORC1 activation.
  
  
  RESULTS
  Increased AA levels enhanced the phosphorylation of ribosomal protein S6 kinase (S6K1), S6, and insulin receptor substrate 1 (IRS-1) on Ser(302) but suppressed Akt and p38 phosphorylation; up-regulated the expression of genes related to gluconeogenesis and fatty acid biosynthesis. mTORC1 inhibition not only inhibited the phosphorylation of mTORC1 downstream targets, but also blunted IRS-1 Ser(302) phosphorylation and restored excessive AAs-suppressed Akt phosphorylation. Rapamycin also inhibited fatty acid biosynthetic and gluconeogenic gene expression.
  
  
  CONCLUSIONS
  High levels of AAs up-regulate hepatic fatty acid biosynthetic gene expression through an mTORC1-dependent manner, while attenuate insulin-mediated repression of gluconeogenesis through elevating IRS-1 Ser(302) phosphorylation, which in turn impairs Akt activation and thereby weakening insulin action. We propose that p38 MAPK probably also involves in these AAs-induced metabolic changes.
authors.affiliation: INRA, UR 1067 Nutrition, Métabolisme, Aquaculture, Pole d'hydrobiologie, CD 918, Saint-Pée-sur-Nivelle, France.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Dai
authors.forename: Stéphane
authors.initials: S
authors.lastname: Panserat
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Plagnes-Juan
authors.forename: Iban
authors.initials: I
authors.lastname: Seiliez
authors.forename: Sandrine
authors.initials: S
authors.lastname: Skiba-Cassy
mesh_terms: D000596:Amino Acids / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D005227:Fatty Acids / Q000819:agonists / Q000096:biosynthesis; D005786:Gene Expression Regulation; D005943:Gluconeogenesis / Q000187:drug effects* / Q000235:genetics; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D050155:Lipogenesis / Q000187:drug effects* / Q000235:genetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014337:Trout / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000596:Amino Acids; D005227:Fatty Acids; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D048051:p38 Mitogen-Activated Protein Kinases; D020123:Sirolimus