title: The TSC complex is required for the benefits of dietary protein restriction on stress resistance in vivo.
abstract: Protein restriction (PR) is important for the benefits of dietary restriction on longevity and stress resistance, but relevant nutrient sensors and downstream effectors in mammals remain poorly defined. We used PR-mediated protection from hepatic ischemia reperfusion injury to probe genetic requirements for the evolutionarily conserved nutrient sensors GCN2 and mTORC1 in stress resistance. One week of PR reduced free amino acids and circulating growth factors, activating GCN2 and mTORC1 repressor tuberous sclerosis complex (TSC). However, although GCN2 was dispensable for PR-induced protection, hepatic TSC1 was required. PR improved hepatic insulin sensitivity in a TSC1-dependent manner prior to ischemia, facilitating increased prosurvival signaling and reduced apoptosis after reperfusion. These benefits were partially abrogated by pharmacological PI3K inhibition or genetic deletion of the insulin receptor in hepatocytes. In conclusion, improved insulin sensitivity upon short-term PR required TSC1, facilitated increased prosurvival signaling after injury, and contributed partially to PR-mediated resistance to clinically relevant ischemia reperfusion injury.
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: Eylul
authors.initials: E
authors.lastname: Harputlugil
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Hine
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: Dorathy
authors.initials: D
authors.lastname: Vargas
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Robertson
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Manning
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA. Electronic address: jmitchel@hsph.harvard.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Mitchell
mesh_terms: D000601:Amino Acids, Essential / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D018753:Diet, Protein-Restricted; D055786:Gene Knockout Techniques; D007333:Insulin Resistance; D007511:Ischemia / Q000378:metabolism; D008099:Liver / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D015427:Reperfusion Injury / Q000178:diet therapy / Q000378:metabolism*; D013312:Stress, Physiological; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D000601:Amino Acids, Essential; D046912:Multiprotein Complexes; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C070634:Eif2ak4 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases