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

Zidek, L. M., Ackermann, T., Hartleben, G., Eichwald, S., Kortman, G., Kiehntopf, M., Leutz, A., Sonenberg, N., Wang, Z-Q., von Maltzahn, J., Mueller, C. & Calkhoven, C. F., Aug-2015, In : Embo Reports. 16, 8, p. 1022-1036 15 p.

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)1022-1036
Number of pages15
JournalEmbo Reports
Volume16
Issue number8
Publication statusPublished - Aug-2015

    Keywords

  • C/EBP beta, calorie restriction, metabolism, mTORC1, translation, BINDING-PROTEIN-BETA, DIET-INDUCED OBESITY, MAMMALIAN LIFE-SPAN, CALORIC RESTRICTION, SERUM TRIGLYCERIDES, INSULIN-RESISTANCE, ADIPONECTIN LEVELS, GENE-EXPRESSION, DOWN-REGULATION, DROSOPHILA

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