Journal ArticleDOI
mTORC1 controls fasting-induced ketogenesis and its modulation by ageing
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TLDR
The findings reveal that m TORC1 is a key regulator of PPARα function and hepatic ketogenesis and suggest a role for mTORC1 activity in promoting the ageing of the liver.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 factors. 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 inhibitor, 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 component, 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 genes, and that suppression of NCoR1 (nuclear receptor co-repressor 1), a co-repressor of PPARα, reactivates ketogenesis in cells and livers with hyperactive mTORC1 signalling. Like livers with activated mTORC1, livers from aged mice have a defect in ketogenesis, 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.read more
Citations
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mTOR Signaling in Growth Control and Disease
TL;DR: The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis as mentioned in this paper, and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration.
Journal ArticleDOI
mTOR signaling in growth control and disease.
TL;DR: Recent advances in understanding of the mTOR pathway are reviewed and pharmacological approaches to treat human pathologies linked to mTOR deregulation are discussed.
Journal ArticleDOI
mTOR Signaling in Growth, Metabolism, and Disease.
TL;DR: Recent advances in understanding of mTOR function, regulation, and importance in mammalian physiology are reviewed and how the mTOR signaling network contributes to human disease is highlighted.
mTOR Signaling in Growth, Metabolism, and Disease
TL;DR: Recent advances in understanding of mTOR function, regulation, and importance in mammalian physiology are reviewed and how the mTOR-signaling network contributes to human disease is highlighted.
OtherDOI
Energy metabolism in the liver
TL;DR: The liver is an essential metabolic organ, and its metabolic function is controlled by insulin and other metabolic hormones, so controlling liver energy metabolism is tightly regulated by neuronal and hormonal signals.
References
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Journal ArticleDOI
Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators
Isabelle Issemann,Stephen Green +1 more
TL;DR: A member of the steroid hormone receptor superfamily of ligand-activated transcription factors is cloned that is activated by a diverse class of rodent hepatocarcinogens that causes proliferation of peroxisomes.
Journal ArticleDOI
Rapamycin fed late in life extends lifespan in genetically heterogeneous mice
David E. Harrison,Randy Strong,Zelton D Sharp,James F. Nelson,Clinton M. Astle,Kevin Flurkey,Nancy L. Nadon,J. Erby Wilkinson,Krystyna Frenkel,Christy S. Carter,Christy S. Carter,Marco Pahor,Marco Pahor,Martin A. Javors,Elizabeth Fernandez,Richard A. Miller +15 more
TL;DR: It is reported that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age.
Journal ArticleDOI
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Béatrice Desvergne,Walter Wahli +1 more
TL;DR: This work has shown that direct expression of PPAR mRNAs in the absence of a specific carrier gene results in down-regulation in the activity of other PPARs, and these properties are consistent with those of a “spatially aggregating substance”.
Journal ArticleDOI
The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1
Yasemin Sancak,Timothy R. Peterson,Yoav D. Shaul,Robert A. Lindquist,Carson C. Thoreen,Liron Bar-Peled,David M. Sabatini,David M. Sabatini +7 more
TL;DR: It is found that the Rag proteins—a family of four related small guanosine triphosphatases (GTPases)—interact with mTORC1 in an amino acid–sensitive manner and are necessary for the activation of the m TORC1 pathway by amino acids.