In vivo relevance of mTOR controlled C/EBPbeta mRNA translation for metabolic health and lifespan determination
Final Report Abstract
Reducing calorie intake improves health and may extend lifespan in virtually all animal species tested. Furthermore, a prominent feature of calorie restriction is that it results in less cancer. Not surprisingly, these findings fuel the hope of being able to improve our health and live longer. Our aim is to understand the underlying molecular mechanisms and to find possible drug targets to develop therapies against metabolic disease and cancer. The so-called mTORC1 complex that resides in our cells senses the amount and kind of nutrients (food) that are available and instructs the cell to either grow and store energy (plenty nutrients available) or to maintain and survive (under nutritional harsh conditions). We have discovered that a gene-regulator protein called LIP is instructed by mTORC1 to regulate those genes that let cells store excess of nutrients in the form of body fat. The LIP-coding gene (called CEBPB) contains a small regulatory element, called uORF, which senses the activity of mTORC1; this element brings LIP under control of mTORC1. We experimentally removed the uORF in mice rendering LIP independent from mTORC1. Although mTORC1 still can sense the consumed food it cannot ‘instruct’ the LIP-coding gene to produce LIP and turn on the fat storage program. Intriguingly, although these mice eat similarly unrestricted as normal control mice their body thinks that it is on a reduced calorie diet and burns fat rather than carbohydrates for energy production. That’s why these LIP-deficient mutant mice are healthier than normal mice. They are leaner with more healthy metabolic parameters, being less prone to develop diabetes type II and having a better physical condition. Moreover, the LIP-deficient mice have less cancer and live longer. This discovery was communicated to the broader public through articles in, the Dutch newspaper “De Volkskrant” of 06/07/2015 “Groningse muis eet alles en blijft toch gezond”, and through numerous German and international articles through press releases, e.g. Atlas of Science (http://atlasofscience.org/a-genetic-switch-for/), Medizin Aspekte “Schlank aber Satt” (http://medizin-aspekte.de), Der Standard “Schlank und Satt” (http://derstandard.at). The study in mice is probably useful for humans, and if we could develop drugs that lower LIP levels these may improve human metabolic health and reduce cancer. Therefore we set up a screen to identify such pharmacological compounds in collaboration with Fraunhofer IME ScreeningPort, Hamburg. From a first screen we identified a drug that shows the anticipated beneficial metabolic effects in the laboratory. This drug is currently under further investigation. Taken together, we show that the developed drug screening system is useful to search for candidate drugs that may be further developed into novel anti-cancer drugs and/or drugs against (age-related) metabolic diseases.
Publications
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(2015) Deficiency in mTORC1-controlled C/EBPβ-mRNA translation improves metabolic health in mice. EMBO Reports 16, 1022-1036
Zidek, L. M., Ackermann, T. Hartleben, G., Eichwald, S., Kortman, G., Kiehntopf, M., Leutz, A., Sonenberg N., Wang, Z-Q, von Maltzahn, J., Müller, C., and Calkhoven, C.F.
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(2017) A screening strategy for the discovery of drugs that reduce C/EBPβ-LIP translation with potential calorie restriction mimetic properties. Scientific Reports volume 7, Article number: 42603
Zaini, M. A., Müller, C., Ackermann, T., Reinshagen, J., Kortman, G., Pless, O., Calkhoven, C.F.
