title: Chromatin recruitment of activated AMPK drives fasting response genes co-controlled by GR and PPARα.
abstract: Adaptation to fasting involves both Glucocorticoid Receptor (GRα) and Peroxisome Proliferator-Activated Receptor α (PPARα) activation. Given both receptors can physically interact we investigated the possibility of a genome-wide cross-talk between activated GR and PPARα, using ChIP- and RNA-seq in primary hepatocytes. Our data reveal extensive chromatin co-localization of both factors with cooperative induction of genes controlling lipid/glucose metabolism. Key GR/PPAR co-controlled genes switched from transcriptional antagonism to cooperativity when moving from short to prolonged hepatocyte fasting, a phenomenon coinciding with gene promoter recruitment of phosphorylated AMP-activated protein kinase (AMPK) and blocked by its pharmacological inhibition. In vitro interaction studies support trimeric complex formation between GR, PPARα and phospho-AMPK. Long-term fasting in mice showed enhanced phosphorylation of liver AMPK and GRα Ser211. Phospho-AMPK chromatin recruitment at liver target genes, observed upon prolonged fasting in mice, is dampened by refeeding. Taken together, our results identify phospho-AMPK as a molecular switch able to cooperate with nuclear receptors at the chromatin level and reveal a novel adaptation mechanism to prolonged fasting.
authors: Receptor Research Laboratories, Nuclear Receptor Lab, Medical Biotechnology Center, VIB, 9000 Ghent, Belgium.|Department of Biochemistry, Ghent University, 9000 Ghent, Belgium.
authors: Dariusz
authors: D
authors: Ratman
authors: Receptor Research Laboratories, Nuclear Receptor Lab, Medical Biotechnology Center, VIB, 9000 Ghent, Belgium.|Department of Biochemistry, Ghent University, 9000 Ghent, Belgium.
authors: Viacheslav
authors: V
authors: Mylka
authors: Receptor Research Laboratories, Nuclear Receptor Lab, Medical Biotechnology Center, VIB, 9000 Ghent, Belgium.|Department of Biochemistry, Ghent University, 9000 Ghent, Belgium.
authors: Nadia
authors: N
authors: Bougarne
authors: UNIV LILLE, 59000 Lille, France.|INSERM UMR 1011, 59000 Lille, France.|European Genomic Institute for Diabetes E.G.I.D., FR 3508, 59000 Lille, France.|Institut Pasteur de Lille, 59000 Lille, France.
authors: Michal
authors: M
authors: Pawlak
authors: UNIV LILLE, 59000 Lille, France.|INSERM UMR 1011, 59000 Lille, France.|European Genomic Institute for Diabetes E.G.I.D., FR 3508, 59000 Lille, France.|Institut Pasteur de Lille, 59000 Lille, France.
authors: Sandrine
authors: S
authors: Caron
authors: UNIV LILLE, 59000 Lille, France.|INSERM UMR 1011, 59000 Lille, France.|European Genomic Institute for Diabetes E.G.I.D., FR 3508, 59000 Lille, France.|Institut Pasteur de Lille, 59000 Lille, France.
authors: Nathalie
authors: N
authors: Hennuyer
authors: UNIV LILLE, 59000 Lille, France.|INSERM UMR 1011, 59000 Lille, France.|European Genomic Institute for Diabetes E.G.I.D., FR 3508, 59000 Lille, France.|Institut Pasteur de Lille, 59000 Lille, France.
authors: Réjane
authors: R
authors: Paumelle
authors: Receptor Research Laboratories, Nuclear Receptor Lab, Medical Biotechnology Center, VIB, 9000 Ghent, Belgium.|Department of Biochemistry, Ghent University, 9000 Ghent, Belgium.
authors: Lode
authors: L
authors: De Cauwer
authors: Receptor Research Laboratories, Nuclear Receptor Lab, Medical Biotechnology Center, VIB, 9000 Ghent, Belgium.|Department of Biochemistry, Ghent University, 9000 Ghent, Belgium.
authors: Jonathan
authors: J
authors: Thommis
authors: de Duve Institute and Université catholique de Louvain, 1200 Brussels, Belgium.
authors: Mark H
authors: MH
authors: Rider
authors: Inflammation Research Center, VIB, 9052 Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
authors: Claude
authors: C
authors: Libert
authors: Department of Biochemistry, Ghent University, 9000 Ghent, Belgium.|Receptor Research Laboratories, Cytokine Receptor Lab, Medical Biotechnology Center, VIB, 9000 Ghent, Belgium.
authors: Sam
authors: S
authors: Lievens
authors: Department of Biochemistry, Ghent University, 9000 Ghent, Belgium.|Receptor Research Laboratories, Cytokine Receptor Lab, Medical Biotechnology Center, VIB, 9000 Ghent, Belgium.
authors: Jan
authors: J
authors: Tavernier
authors: UNIV LILLE, 59000 Lille, France.|INSERM UMR 1011, 59000 Lille, France.|European Genomic Institute for Diabetes E.G.I.D., FR 3508, 59000 Lille, France.|Institut Pasteur de Lille, 59000 Lille, France.|CHU Lille, Department of Biology, 59000 Lille, France.
authors: Bart
authors: B
authors: Staels
authors: Receptor Research Laboratories, Nuclear Receptor Lab, Medical Biotechnology Center, VIB, 9000 Ghent, Belgium karolien.debosscher@vib-ugent.be karolien.debosscher@ugent.be.|Department of Biochemistry, Ghent University, 9000 Ghent, Belgium.
authors: Karolien
authors: K
authors: De Bosscher
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D005215:Fasting; D022781:Hepatocytes / Q000378:metabolism; D050356:Lipid Metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047493:PPAR alpha / Q000502:physiology*; D021381:Protein Transport; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D017422:Sequence Analysis, DNA; D015533:Transcriptional Activation; D059467:Transcriptome
chemical_list: D002843:Chromatin; D047493:PPAR alpha; D011965:Receptors, Glucocorticoid; D000263:Adenylate Kinase