Repeated fasting events sensitize enhancers, transcription factor activity and gene expression to support augmented ketogenesis
Mammals withstand frequent and prolonged fasting periods due to hepatic production of glucose and ketone bodies. Because the fasting response is transcriptionally regulated, we asked whether enhancer dynamics impose a transcriptional program during recurrent fasting and whether this generates effects distinct from a single fasting bout. We found that mice undergoing alternate-day fasting (ADF) respond profoundly differently to a following fasting bout compared to mice first experiencing fasting. Hundreds of genes enabling ketogenesis are 'sensitized' (i.e. induced more strongly by fasting following ADF). Liver enhancers regulating these genes are also sensitized and harbor increased binding of PPARα, the main ketogenic transcription factor. ADF leads to augmented ketogenesis compared to a single fasting bout in wild-type, but not hepatocyte-specific PPARα-deficient mice. Thus, we found that past fasting events are 'remembered' in hepatocytes, sensitizing their enhancers to the next fasting bout and augment ketogenesis. Our findings shed light on transcriptional regulation mediating adaptation to repeated signals.
Authors
- Anne Fougerat (ORCID: https://orcid.org/0009-0000-0305-1880)
- Abedelmajeed Nasereddin (ORCID: https://orcid.org/0000-0001-8162-420X)
- Meirav Bar‐Shimon
- Justine Bruse
- Arnaud Polizzi (ORCID: https://orcid.org/0000-0003-1986-2770)
- Ofer Gover (ORCID: https://orcid.org/0000-0002-8341-6209)
- Noga Korenfeld (ORCID: https://orcid.org/0000-0002-3565-064X)
- Meital Charni‐Natan (ORCID: https://orcid.org/0000-0003-0221-1664)
- Ido Goldstein (ORCID: https://orcid.org/0000-0003-0139-1499)
- Dana Tamar Goldberg (ORCID: https://orcid.org/0000-0001-9674-7907)
- Hervé Guillou (ORCID: https://orcid.org/0000-0002-5363-9081)
- Talia Radushkevitz-Frishman
- Dan Rotaro (ORCID: https://orcid.org/0009-0005-7033-7391)
- Tali Gorbonos (ORCID: https://orcid.org/0009-0005-8892-3444)
- Dorin Marciano-Anaki
Institutions
- Université Toulouse III - Paul Sabatier (FR)
- École Nationale Vétérinaire de Toulouse (FR)
- Université Fédérale de Toulouse Midi-Pyrénées (FR)
- Hebrew University of Jerusalem (IL)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Toxicologie Alimentaire (FR)
Publication Details
- Journal
- Nucleic Acids Research
- Published
- 2024-11-06
- DOI
- https://doi.org/10.1093/nar/gkae1161
- Citations
- 5
- Primary Topic
- Adipose Tissue and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 1.31
Funders
- International Development Research Centre
- Agence Nationale de la Recherche
- Fondation pour la Recherche Médicale
- Israel Science Foundation
- Azrieli Foundation
- Canadian Institutes of Health Research
- H2020 European Research Council