MTORC1 controls fasting-induced ketogenesis and its modulation by ageing

The multi-component mechanistic target of rapamycin complex 1 (mTORC1) kinase is the central node of amammalian 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 pathwayin vivo. Specifically, we have little knowledge regarding the role mTOCR1 has in liver physiology. In fasted animals, the liver performsnumerous functions thatmaintainwhole-bodyhomeostasis, 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.Wefind that liver-specific loss of TSC1 (tuberous sclerosis 1), anmTORC1 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 a), the master transcriptional activator of ketogenic genes ², and that suppression of NCoR1 (nuclear receptor co-repressor 1), a co-repressor of PPARa³, reactivates ketogenesis in cells and livers with hyperactive mTORC1 signalling. Like livers with activated mTORC1, livers from aged mice have a defect in ketogenesis^4,5, which correlates with an increase in mTORC1signalling. Moreover, we showthat 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.