title: Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression.
abstract: Insulin constitutes a principal evolutionarily conserved hormonal axis for maintaining glucose homeostasis; dysregulation of this axis causes diabetes. PGC-1α (peroxisome-proliferator-activated receptor-γ coactivator-1α) links insulin signalling to the expression of glucose and lipid metabolic genes. The histone acetyltransferase GCN5 (general control non-repressed protein 5) acetylates PGC-1α and suppresses its transcriptional activity, whereas sirtuin 1 deacetylates and activates PGC-1α. Although insulin is a mitogenic signal in proliferative cells, whether components of the cell cycle machinery contribute to its metabolic action is poorly understood. Here we report that in mice insulin activates cyclin D1-cyclin-dependent kinase 4 (Cdk4), which, in turn, increases GCN5 acetyltransferase activity and suppresses hepatic glucose production independently of cell cycle progression. Through a cell-based high-throughput chemical screen, we identify a Cdk4 inhibitor that potently decreases PGC-1α acetylation. Insulin/GSK-3β (glycogen synthase kinase 3-beta) signalling induces cyclin D1 protein stability by sequestering cyclin D1 in the nucleus. In parallel, dietary amino acids increase hepatic cyclin D1 messenger RNA transcripts. Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5, which then acetylates and inhibits PGC-1α activity on gluconeogenic genes. Loss of hepatic cyclin D1 results in increased gluconeogenesis and hyperglycaemia. In diabetic models, cyclin D1-Cdk4 is chronically elevated and refractory to fasting/feeding transitions; nevertheless further activation of this kinase normalizes glycaemia. Our findings show that insulin uses components of the cell cycle machinery in post-mitotic cells to control glucose homeostasis independently of cell division.
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Yoonjin
authors.initials: Y
authors.lastname: Lee
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Dominy
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Yoon Jong
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Yale's Mouse Metabolic Phenotyping Center and Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Jurczak
authors.affiliation: Chemical Biology Platform, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02141, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Tolliday
authors.affiliation: Yale's Mouse Metabolic Phenotyping Center and Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Joao Paulo
authors.initials: JP
authors.lastname: Camporez
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Chim
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Ji-Hong
authors.initials: JH
authors.lastname: Lim
authors.affiliation: Yale's Mouse Metabolic Phenotyping Center and Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Ruan
authors.affiliation: Yale's Mouse Metabolic Phenotyping Center and Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Yang
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Francisca
authors.initials: F
authors.lastname: Vazquez
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Sicinski
authors.affiliation: Yale's Mouse Metabolic Phenotyping Center and Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Pere
authors.initials: P
authors.lastname: Puigserver
mesh_terms: D000107:Acetylation; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism; D004789:Enzyme Activation; D005215:Fasting; D017353:Gene Deletion; D005943:Gluconeogenesis / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D008297:Male; D051379:Mice; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D000099224:p300-CBP-Associated Factor
chemical_list: D000596:Amino Acids; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D005947:Glucose; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D051548:Histone Acetyltransferases; D007328:Insulin; D012333:RNA, Messenger; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; C000589598:GCN5 histone acetyltransferase, mouse; D000099224:p300-CBP-Associated Factor; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse; C495902:Cdk4 protein, mouse