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 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.
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A reduction in cellular energy charge, such as during glucose deprivation or fasting, inhibits mTORC1 by AMPK-dependent as well as AMPK-independent pathways, and is required for the generation of ketone bodies in the liver.
“A reduction in cellular energy charge, such as during glucose deprivation or fasting, inhibits mTORC1 by AMPK-dependent as well as AMPK-independent pathways, and is required for the generation of ketone bodies in the liver (277).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [277]
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- Authors
- Sengupta, S., Peterson, T. R., Laplante, M., Oh, S., & Sabatini, D. M.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Sabatini, David M.
- Venue
- Nature
- Published
- 2010-12
- Volume
- 468
- Issue
- 7327
- Pages
- 1100-1104
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2016366885
- Cited by
- 646
- References
- 30
- Citations by year
- 2026: 26 · 2025: 32 · 2024: 47 · 2023: 36 · 2022: 59 · 2021: 47 · 2020: 40 · 2019: 44 · 2018: 44 · 2017: 47 · 2016: 47 · 2015: 33 · 2014: 54 · 2013: 29 · 2012: 40
- FWCI
- 11.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- American Diabetes Association
- National Institutes of Health
- Canadian Institutes of Health Research
- National Cancer Institute (CA129105, CA103866, R01CA103866, R01CA129105)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Physiology › Dietary Effects on Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- mTORC1, fasting, ketogenesis, ketone bodies, aging, PPARα, liver, rapamycin, TSC1, raptors, lifespan, hepatic lipid metabolism, hepatic steatosis, liver fibrosis, liver inflammation, liver regeneration, hepatic glucose production, hepatic gluconeogenesis, hepatic lipogenesis
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Aging, Animals, Cell Line, Fasting, Gene Expression Regulation, Humans, Ketone Bodies, Liver, Mice, Inbred C57BL, Proteins, Mice, Knockout, Multiprotein Complexes, PPAR alpha, Mice, Nuclear Receptor Co-Repressor 1, TOR Serine-Threonine Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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