Deficiency in mTORC 1‐controlled C/ EBP β ‐ 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.

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

“…Immunoblotting was performed as described earlier (Zidek et al , 2015) with the following antibodies: from Cell Signaling Technology, anti‐TSC1 (#4906), anti‐TSC2 (#4308); anti‐pS6K (Thr389) (#9206) and (Thr389) (#9234), anti‐S6K (#9202), anti‐pS6 (Ser235/236) (#2211), anti‐S6 (#2317), anti‐pSAPK/JNK (Thr183/Tyr185) (#9251); anti‐p‐4E‐BP1 (T37/46) (#9459); anti‐p‐AKT (Ser473) (#4060); anti‐AKT (#9272); anti‐MYC (#5605); from Sigma‐Aldrich, anti‐β‐actin (A3853); from Santa Cruz Biotechnology, anti‐α‐tubulin (sc‐8035), anti‐TSC2 (sc‐893), anti‐MYC (sc‐40), anti‐SAPK/JNK (sc‐571); and from MP Biomedicals, anti‐β‐actin (#69100). Bands were visualized by chemoluminescence (Western Lightning Plus‐ECL, Perkin Elmer).…”

Reduced C/ EBP β‐ LIP translation improves metabolic health

“…There is thus a strong need for novel therapeutic options aimed at treating obesity. Zidek et al [1] demonstrate now that inhibition of mTORC1 in cultured cells by rapamycin treatment or by knockdown of the essential mTORC1 component raptor decreases C/ EBPb-LIP translation without altering C/ EBPb-LAP levels. Hence, using therapeutic agents that mimic the metabolic effects of CR could be an efficient way to treat obesity and decrease the risk of obesity-associated diseases.…”

“…In this issue of EMBO Reports, Zidek et al [1] describe that inhibition of mammalian TORC1 (mTORC1) leads to decreased translation of CCAAT/ enhancer-binding protein b (C/EBPb)-liver inhibitory protein (LIP). It is however not fully elucidated which cellular processes downstream of TORC1 are the main regulators of metabolic health.…”

“…Zidek et al [1] thus report that reduced C/EBPb-LIP translation is a novel mTORC1-regulated process that could play a major role in mediating the beneficial metabolic effects of caloric restriction. In this issue of EMBO Reports, Zidek et al [1] identify a novel mTORC1-regulated process that might be involved in mediating the beneficial effects of CR on metabolism [4] demonstrated that mTORC1 signaling stimulates eIF4E-mediated translation of C/EBPb-LIP. Moreover, in the last decades, the prevalence of obesity has dramatically increased worldwide [2].…”

“…However, to generate CR-mimetic compounds, it is important to understand the molecular signaling pathways that mediate the CR-induced effects on metabolism. Zidek et al [1] demonstrate that the uORF in the 5 0 UTR of C/EBPb mRNA is necessary for mTORC1-4EBP-eIF4E-mediated stimulation of C/EBPb-LIP translation. Importantly, several TORC1-regulated processes, such as protein synthesis and autophagy, have been implicated in the metabolic effects of CR (reviewed in [3]).…”