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mTORC1 controls fasting-induced ketogenesis and its modulation by ageing

Author

Listed:
  • Shomit Sengupta

    (Whitehead Institute for Biomedical Research, Nine Cambridge Center
    Howard Hughes Medical Institute, Massachusetts Institute of Technology
    The David H. Koch Institute for Integrative Cancer Research at MIT)

  • Timothy R. Peterson

    (Whitehead Institute for Biomedical Research, Nine Cambridge Center
    Howard Hughes Medical Institute, Massachusetts Institute of Technology
    The David H. Koch Institute for Integrative Cancer Research at MIT)

  • Mathieu Laplante

    (Whitehead Institute for Biomedical Research, Nine Cambridge Center
    Howard Hughes Medical Institute, Massachusetts Institute of Technology
    The David H. Koch Institute for Integrative Cancer Research at MIT)

  • Stephanie Oh

    (Whitehead Institute for Biomedical Research, Nine Cambridge Center
    Howard Hughes Medical Institute, Massachusetts Institute of Technology
    The David H. Koch Institute for Integrative Cancer Research at MIT)

  • David M. Sabatini

    (Whitehead Institute for Biomedical Research, Nine Cambridge Center
    Howard Hughes Medical Institute, Massachusetts Institute of Technology
    The David H. Koch Institute for Integrative Cancer Research at MIT)

Abstract

mTORC1 in the fasting liver During periods of fasting, the liver breaks down fatty acids to produce acetone and other ketone bodies that the peripheral tissues can use as a source of energy. A study of the role in the liver of mTORC1, the target of the immunosuppressant rapamycin, shows that fasting inhibits the activity of multicomponent mTORC1. Inhibition of mTORC1 is required for activation of PPARα, a master regulator that switches on genes involved in ketogenesis. Livers from aged mice have increased mTORC1 signalling, reduced PPARα activity and reduced ketone production. The observation that mTORC1 promotes an ageing phenotype in the liver fits well with the observation that inhibition of this pathway increases lifespan in several organisms.

Suggested Citation

  • Shomit Sengupta & Timothy R. Peterson & Mathieu Laplante & Stephanie Oh & David M. Sabatini, 2010. "mTORC1 controls fasting-induced ketogenesis and its modulation by ageing," Nature, Nature, vol. 468(7327), pages 1100-1104, December.
    • Handle: RePEc:nat:nature:v:468:y:2010:i:7327:d:10.1038_nature09584
    DOI: 10.1038/nature09584
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    Citations

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    Cited by:

    1. Gloria Ursino & Giorgio Ramadori & Anna Höfler & Soline Odouard & Pryscila D. S. Teixeira & Florian Visentin & Christelle Veyrat-Durebex & Giulia Lucibello & Raquel Firnkes & Serena Ricci & Claudia R., 2022. "Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Hui Xia & Catherine R. Dufour & Younes Medkour & Charlotte Scholtes & Yonghong Chen & Christina Guluzian & Wafa B’chir & Vincent Giguère, 2023. "Hepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression in male mice," Nature Communications, Nature, vol. 14(1), pages 1-24, December.
    3. Vasiliki Karalis & Franklin Caval-Holme & Helen S. Bateup, 2022. "Raptor downregulation rescues neuronal phenotypes in mouse models of Tuberous Sclerosis Complex," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    4. Min Yan Shi & Hwang Chan Yu & Chang Yeob Han & In Hyuk Bang & Ho Sung Park & Kyu Yun Jang & Sangkyu Lee & Jeong Bum Son & Nam Doo Kim & Byung-Hyun Park & Eun Ju Bae, 2023. "p21-activated kinase 4 suppresses fatty acid β-oxidation and ketogenesis by phosphorylating NCoR1," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    5. Evangelia Lekka & Aleksandra Kokanovic & Simone Mosole & Gianluca Civenni & Sandro Schmidli & Artur Laski & Alice Ghidini & Pavithra Iyer & Christian Berk & Alok Behera & Carlo V. Catapano & Jonathan , 2022. "Pharmacological inhibition of Lin28 promotes ketogenesis and restores lipid homeostasis in models of non-alcoholic fatty liver disease," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    6. Ana Belén Plata-Gómez & Lucía Prado-Rivas & Alba Sanz & Nerea Deleyto-Seldas & Fernando García & Celia Calle Arregui & Camila Silva & Eduardo Caleiras & Osvaldo Graña-Castro & Elena Piñeiro-Yáñez & Jo, 2024. "Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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