Peroxisome proliferator–activated receptor α mediates the adaptive response to fasting
Open accessAbstract
Prolonged deprivation of food induces dramatic changes in mammalian metabolism, including the release of large amounts of fatty acids from the adipose tissue, followed by their oxidation in the liver. The nuclear receptor known as peroxisome proliferator-activated receptor alpha (PPARalpha) was found to play a role in regulating mitochondrial and peroxisomal fatty acid oxidation, suggesting that PPARalpha may be involved in the transcriptional response to fasting. To investigate this possibility, PPARalpha-null mice were subjected to a high fat diet or to fasting, and their responses were compared with those of wild-type mice. PPARalpha-null mice chronically fed a high fat diet showed a massive accumulation of lipid in their livers. A similar phenotype was noted in PPARalpha-null mice fasted for 24 hours, who also displayed severe hypoglycemia, hypoketonemia, hypothermia, and elevated plasma free fatty acid levels, indicating a dramatic inhibition of fatty acid uptake and oxidation. It is shown that to accommodate the increased requirement for hepatic fatty acid oxidation, PPARalpha mRNA is induced during fasting in wild-type mice. The data indicate that PPARalpha plays a pivotal role in the management of energy stores during fasting. By modulating gene expression, PPARalpha stimulates hepatic fatty acid oxidation to supply substrates that can be metabolized by other tissues.
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OEA activates PPAR-alpha, a major regulator of lipid metabolism activated to induce a metabolic adaptive response to prolonged fasting.
“Since OEA has been shown to activate peroxisome proliferator-activated receptor alpha (PPAR-alpha) (Guzmán et al., 2004), a major regulator of lipid metabolism that is activated to induce a metabolic adaptive response to prolonged fasting (Kersten et al., 1999)”
From Sleep restriction alters plasma endocannabinoids concentrations before but not after exercise in humans (2016) · cites this paper as Kersten et al., 1999
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- Authors
- Kersten, S., Seydoux, J., Peters, J. M., Gonzalez, F. J., Desvergne, B., & Wahli, W.
- Affiliations
- University of Lausanne (CH)
- University of Geneva (CH)
- National Institutes of Health (US)
- Corresponding author
- Wahli, Walter
- Venue
- Journal of Clinical Investigation
- Published
- 1999-06-01
- Volume
- 103
- Issue
- 11
- Pages
- 1489-1498
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC408372
- OpenAlex
- W2103116278
- Cited by
- 1,649
- References
- 50
- Citations by year
- 2026: 29 · 2025: 44 · 2024: 44 · 2023: 39 · 2022: 50 · 2021: 61 · 2020: 66 · 2019: 63 · 2018: 58 · 2017: 66 · 2016: 70 · 2015: 60 · 2014: 82 · 2013: 74 · 2012: 72
- FWCI
- 16.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- PPARα, fasting, hepatic fatty acid oxidation, peroxisomal fatty acid oxidation, mitochondrial fatty acid oxidation, PPARalpha-null mice, high-fat diet, hepatic lipid accumulation, hypoglycemia, hypothermia, plasma free fatty acids, energy metabolism, transcriptional regulation
- MeSH terms
- Fatty Acid-Binding Protein 7, Adaptation, Physiological, Animals, Apolipoproteins B, Apolipoproteins E, Carnitine O-Palmitoyltransferase, Carrier Proteins, Dietary Fats, Fasting, Fatty Acids, Fatty Liver, Gene Expression Regulation, Hormones, Hypothermia, Induced, Lipoproteins, VLDL, Microbodies, Neoplasm Proteins, Nerve Tissue Proteins, Oxidation-Reduction, Phenotype, RNA, Messenger, Transcription Factors, Transcription, Genetic, Signal Transduction, Gene Expression, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Myelin P2 Protein, Acyl-CoA Dehydrogenase, Fatty Acid Desaturases, Fatty Acid-Binding Proteins, Mice
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