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mTORC1 controls fasting-induced ketogenesis and its modulation by ageing

Abstract

The multi-component mechanistic target of rapamycin complex 1 (mTORC1) kinase is the central node of a mammalian pathway that coordinates cell growth with the availability of nutrients, energy and growth factors1. Progress has been made in the identification of mTORC1 pathway components and in understanding their functions in cells, but there is relatively little known about the role of the pathway in vivo. Specifically, we have little knowledge regarding the role mTOCR1 has in liver physiology. In fasted animals, the liver performs numerous functions that maintain whole-body homeostasis, including the production of ketone bodies for peripheral tissues to use as energy sources. Here we show that mTORC1 controls ketogenesis in mice in response to fasting. We find that liver-specific loss of TSC1 (tuberous sclerosis 1), an mTORC1 inhibitor1, leads to a fasting-resistant increase in liver size, and to a pronounced defect in ketone body production and ketogenic gene expression on fasting. The loss of raptor (regulatory associated protein of mTOR, complex 1) an essential mTORC1 component1, has the opposite effects. In addition, we find that the inhibition of mTORC1 is required for the fasting-induced activation of PPARα (peroxisome proliferator activated receptor α), the master transcriptional activator of ketogenic genes2, and that suppression of NCoR1 (nuclear receptor co-repressor 1), a co-repressor of PPARα3, reactivates ketogenesis in cells and livers with hyperactive mTORC1 signalling. Like livers with activated mTORC1, livers from aged mice have a defect in ketogenesis4,5, which correlates with an increase in mTORC1 signalling. Moreover, we show that the suppressive effects of mTORC1 activation and ageing on PPARα activity and ketone production are not additive, and that mTORC1 inhibition is sufficient to prevent the ageing-induced defect in ketogenesis. Thus, our findings reveal that mTORC1 is a key regulator of PPARα function and hepatic ketogenesis and suggest a role for mTORC1 activity in promoting the ageing of the liver.

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Figure 1: In the liver, mTORC1 activity is sensitive to fasting and feeding and regulates organ size.
Figure 2: mTORC1 inhibits ketogenesis and PPARα activity in a liver autonomous fashion.
Figure 3: mTORC1 requires the NCoR1 corepressor to inhibit PPARα function.
Figure 4: mTORC1 mediates the ageing-induced inhibition of PPARα function and ketone production.

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Acknowledgements

We thank S. Biddinger and C.R. Kahn for providing the IrloxP/loxP and Li-IrKO mice; D. Kwiatkowski for the Tsc1loxP/loxP mice; R. Zoncu for assistance with imaging experiments and image analysis; F. Reinhardt for assistance in animal virus injections; and T. Jacks, L. Guarente, V. Mootha and members of the Sabatini laboratory for support and discussions. This research was supported by fellowships from the American Diabetes Association and Ludwig Cancer Fund to T.R.P.; a fellowship from the Canadian Institutes of Health Research to M.L.; and NIH grants CA103866 and CA129105 to D.M.S. D.M.S. is an investigator of the Howard Hughes Medical Institute.

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S.S. and D.M.S. conceived the project and designed the experiments, S.S. performed the experiments, and T.R.P. aided in generating the Li-RapKO mice and adenovirus preparations. M.L. assisted in metabolite measurements and animal dissections. S.O. assisted with animal dissections and husbandry. S.S. wrote and D.M.S. edited the manuscript.

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Correspondence to David M. Sabatini.

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The authors declare no competing financial interests.

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Sengupta, S., Peterson, T., Laplante, M. et al. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 468, 1100–1104 (2010). https://doi.org/10.1038/nature09584

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