title: Role of GCN2-Independent Signaling Through a Noncanonical PERK/NRF2 Pathway in the Physiological Responses to Dietary Methionine Restriction.
abstract: Restricting availability of essential amino acids (EAAs) limits aminoacylation of tRNAs by their cognate EAAs and activates the nutrient-sensing kinase, general control nonderepressible 2 (GCN2). Activated GCN2 phosphorylates eukaryotic initiation factor 2 (eIF2), altering gene-specific translation and initiating a transcriptional program collectively described as the integrated stress response (ISR). Central GCN2 activation by EAA deprivation is also linked to an acute aversive feeding response. Dietary methionine restriction (MR) produces a well-documented series of physiological responses (increased energy intake and expenditure, decreased adiposity, and increased insulin sensitivity), but the role of GCN2 in mediating them is unknown. Using Gcn2(-/-) mice, we found that the absence of GCN2 had no effect on the ability of MR to reduce body weight or adiposity, increase energy intake and expenditure, increase hepatic transcription and release of fibroblast growth factor 21, or improve insulin sensitivity. Interestingly, hepatic eIF2 phosphorylation by MR was uncompromised in Gcn2(-/-) mice. Instead, protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) was activated in both intact and Gcn2(-/-) mice. PERK activation corresponded with induction of the ISR and the nuclear respiratory factor 2 antioxidant program but not ER stress. These data uncover a novel glutathione-sensing mechanism that functions independently of GCN2 to link dietary MR to its metabolic phenotype.
authors.affiliation: Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA.
authors.forename: Desiree
authors.initials: D
authors.lastname: Wanders
authors.affiliation: Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA.
authors.forename: Kirsten P
authors.initials: KP
authors.lastname: Stone
authors.affiliation: Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Forney
authors.affiliation: Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA.
authors.forename: Cory C
authors.initials: CC
authors.lastname: Cortez
authors.affiliation: Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA.
authors.forename: Kelly N
authors.initials: KN
authors.lastname: Dille
authors.affiliation: Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Simon
authors.affiliation: Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA.
authors.forename: Mark
authors.initials: M
authors.lastname: Xu
authors.affiliation: Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA.
authors.forename: Elisabeth C
authors.initials: EC
authors.lastname: Hotard
authors.affiliation: Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ.
authors.forename: Inna A
authors.initials: IA
authors.lastname: Nikonorova
authors.affiliation: Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ.
authors.forename: Ashley P
authors.initials: AP
authors.lastname: Pettit
authors.affiliation: Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ.
authors.forename: Tracy G
authors.initials: TG
authors.lastname: Anthony
authors.affiliation: Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA thomas.gettys@pbrc.edu.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Gettys
mesh_terms: D000818:Animals; D059865:Endoplasmic Reticulum Stress; D015852:Eukaryotic Initiation Factor-2; D008099:Liver / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D046249:Transfer RNA Aminoacylation; D019892:eIF-2 Kinase / Q000502:physiology*
chemical_list: D015852:Eukaryotic Initiation Factor-2; D008715:Methionine; D051267:NF-E2-Related Factor 2; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; C495636:Nfe2l2 protein, mouse; C070634:Eif2ak4 protein, mouse