title: Deficiency in mTORC1-controlled C/EBPβ-mRNA translation improves metabolic health in mice.
abstract: The mammalian target of rapamycin complex 1 (mTORC1) is a central regulator of physiological adaptations in response to changes in nutrient supply. Major downstream targets of mTORC1 signalling are the mRNA translation regulators p70 ribosomal protein S6 kinase 1 (S6K1p70) and the 4E-binding proteins (4E-BPs). However, little is known about vertebrate mRNAs that are specifically controlled by mTORC1 signalling and are engaged in regulating mTORC1-associated physiology. Here, we show that translation of the CCAAT/enhancer binding protein beta (C/EBPβ) mRNA into the C/EBPβ-LIP isoform is suppressed in response to mTORC1 inhibition either through pharmacological treatment or through calorie restriction. Our data indicate that the function of 4E-BPs is required for suppression of LIP. Intriguingly, mice lacking the cis-regulatory upstream open reading frame (uORF) in the C/EBPβ-mRNA, which is required for mTORC1-stimulated translation into C/EBPβ-LIP, display an improved metabolic phenotype with features also found under calorie restriction. Thus, our data suggest that translational adjustment of C/EBPβ-isoform expression is one of the key processes that direct metabolic adaptation in response to changes in mTORC1 activity.
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute, Jena, Germany.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Zidek
authors.affiliation: European Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Tobias
authors.initials: T
authors.lastname: Ackermann
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute, Jena, Germany European Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Götz
authors.initials: G
authors.lastname: Hartleben
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute, Jena, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Eichwald
authors.affiliation: European Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Gertrud
authors.initials: G
authors.lastname: Kortman
authors.affiliation: Department of Clinical Chemistry and Laboratory Diagnostics, University Hospital Jena, Jena, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kiehntopf
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Leutz
authors.affiliation: Department of Biochemistry & Goodman Cancer Research Center, McGill University, Montreal, QC, Canada.
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute, Jena, Germany.
authors.forename: Zhao-Qi
authors.initials: ZQ
authors.lastname: Wang
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute, Jena, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: von Maltzahn
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute, Jena, Germany European Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Christine
authors.initials: C
authors.lastname: Müller
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute, Jena, Germany European Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands c.f.calkhoven@umcg.nl.
authors.forename: Cornelis F
authors.initials: CF
authors.lastname: Calkhoven
mesh_terms: D050156:Adipogenesis / Q000235:genetics; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D031204:Caloric Restriction; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D050356:Lipid Metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016366:Open Reading Frames; D010084:Oxidation-Reduction; D010641:Phenotype; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C545013:Cebpb protein, mouse; D005227:Fatty Acids; D046912:Multiprotein Complexes; D020033:Protein Isoforms; D012333:RNA, Messenger; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: C/EBPβ; calorie restriction; mTORC1; metabolism; translation