title: Amino Acid-Induced Activation of mTORC1 in Rat Liver Is Attenuated by Short-Term Consumption of a High-Fat Diet.
abstract: BACKGROUND
  The chronic activation of the mechanistic (mammalian) target of rapamycin in complex 1 (mTORC1) in response to excess nutrients contributes to obesity-associated pathologies.
  
  
  OBJECTIVE
  To understand the initial events that ultimately lead to obesity-associated pathologies, the present study assessed mTORC1 responses in the liver after a relatively short exposure to a high-fat diet (HFD).
  
  
  METHODS
  Male, obesity-prone rats were meal-trained to consume either a control (CON; 10% of energy from fat) diet or an HFD (60% of energy from fat) for 2 wk. Livers were collected and analyzed for mTORC1 signaling [assessed by changes in phosphorylation of 70-kDa ribosomal protein S6 kinase 1 (p70S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1)] and potential regulatory mechanisms, including changes in the association of Ras-related GTP binding (Rag) A and RagC with mechanistic target of rapamycin (mTOR) and expression of Sestrin1, Sestrin2, and Sestrin3.
  
  
  RESULTS
  Feeding-induced activation of mTORC1 was blunted in the livers of rats fed the HFD compared with those fed the CON diet (p70S6K1 phosphorylation, 19% of CON; 4E-BP1 phosphorylation, 61% of CON). The attenuated response was not due to a change in a kinase also referred to as protein kinase B (Akt) signaling but rather to resistance to amino acid-induced activation of mTORC1, as evidenced by a reduction in the interaction of RagA (69% of CON) and RagC (66% of CON) with mTOR and enhanced expression of the mTORC1 repressors Sestrin2 (132% of CON) and Sestrin3 (143% of CON). The consumption of an HFD led to impaired amino acid-induced activation of mTORC1 as assessed in livers perfused in situ with medium containing various concentrations of amino acids.
  
  
  CONCLUSIONS
  These results in rats support a model in which the initial response of the liver to an HFD is an attenuation of, rather than the expected activation of, mTORC1. The initial response likely represents a counterregulatory mechanism to handle the onset of excess nutrients and is caused by enhanced expression of Sestrin2 and Sestrin3, which, in turn, leads to impaired Rag signaling, resulting in resistance to amino acid-induced activation of mTORC1.
authors.affiliation: Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA skimball@psu.edu.
authors.forename: Scot R
authors.initials: SR
authors.lastname: Kimball
authors.affiliation: Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA.
authors.forename: Suhana
authors.initials: S
authors.lastname: Ravi
authors.affiliation: Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA.
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Gordon
authors.affiliation: Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Dennis
authors.affiliation: Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA.
authors.forename: Leonard S
authors.initials: LS
authors.lastname: Jefferson
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D047468:Immunoprecipitation; D008099:Liver / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000084622:Sestrins
chemical_list: D000596:Amino Acids; D001786:Blood Glucose; D018797:Cell Cycle Proteins; D006360:Heat-Shock Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D012097:Repressor Proteins; D058570:TOR Serine-Threonine Kinases; C586973:Sesn1 protein, rat; D000084622:Sestrins; C583887:Sesn2 protein, rat; C097056:Rraga protein, rat
keywords: high-fat diet; liver; mTORC1; obesity; signaling