title: Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3.
abstract: Chronic activation of mammalian target of rapamycin complex 1 (mTORC1) and p70 S6 kinase (S6K) in response to hypernutrition contributes to obesity-associated metabolic pathologies, including hepatosteatosis and insulin resistance. Sestrins are stress-inducible proteins that activate AMP-activated protein kinase (AMPK) and suppress mTORC1-S6K activity, but their role in mammalian physiology and metabolism has not been investigated. We show that Sestrin2--encoded by the Sesn2 locus, whose expression is induced upon hypernutrition--maintains metabolic homeostasis in liver of obese mice. Sesn2 ablation exacerbates obesity-induced mTORC1-S6K activation, glucose intolerance, insulin resistance, and hepatosteatosis, all of which are reversed by AMPK activation. Furthermore, concomitant ablation of Sesn2 and Sesn3 provokes hepatic mTORC1-S6K activation and insulin resistance even in the absence of nutritional overload and obesity. These results demonstrate an important homeostatic function for the stress-inducible Sestrin protein family in the control of mammalian lipid and glucose metabolism.
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, San Diego, CA 92093, USA. leeju@umich.edu
authors.forename: Jun Hee
authors.initials: JH
authors.lastname: Lee
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Budanov
authors.forename: Saswata
authors.initials: S
authors.lastname: Talukdar
authors.forename: Eek Joong
authors.initials: EJ
authors.lastname: Park
authors.forename: Hae Li
authors.initials: HL
authors.lastname: Park
authors.forename: Hwan-Woo
authors.initials: HW
authors.lastname: Park
authors.forename: Gautam
authors.initials: G
authors.lastname: Bandyopadhyay
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Mariam
authors.initials: M
authors.lastname: Aghajan
authors.forename: Insook
authors.initials: I
authors.lastname: Jang
authors.forename: Amber M
authors.initials: AM
authors.lastname: Wolfe
authors.forename: Guy A
authors.initials: GA
authors.lastname: Perkins
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ellisman
authors.forename: Ethan
authors.initials: E
authors.lastname: Bier
authors.forename: Miriam
authors.initials: M
authors.lastname: Scadeng
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Jerrold
authors.initials: J
authors.lastname: Olefsky
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D004734:Energy Metabolism / Q000502:physiology*; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D007333:Insulin Resistance / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000502:physiology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D010544:Peroxidases; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D000084622:Sestrins
chemical_list: D055372:AMP-Activated Protein Kinases; D006360:Heat-Shock Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D010544:Peroxidases; D011506:Proteins; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C549101:Sesn3 protein, mouse; D000084622:Sestrins; C529380:Sesn2 protein, mouse