Deficiency in mTORC1-controlled C/EBP beta-mRNA translation improves metabolic health in mice

Laura M. Zidek, Tobias Ackermann, Goetz Hartleben, Sabrina Eichwald, Gertrud Kortman, Michael Kiehntopf, Achim Leutz, Nahum Sonenberg, Zhao-Qi Wang, Julia von Maltzahn, Christine Mueller, Cornelis F. Calkhoven*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

28 Citaten (Scopus)
187 Downloads (Pure)

Samenvatting

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/EBP beta) mRNA into the C/EBP beta-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/EBP beta-mRNA, which is required for mTORC1-stimulated translation into C/EBP beta-LIP, display an improved metabolic phenotype with features also found under calorie restriction. Thus, our data suggest that translational adjustment of C/EBP beta-isoform expression is one of the key processes that direct metabolic adaptation in response to changes in mTORC1 activity.

Originele taal-2English
Pagina's (van-tot)1022-1036
Aantal pagina's15
TijdschriftEmbo Reports
Volume16
Nummer van het tijdschrift8
DOI's
StatusPublished - aug.-2015

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