Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression

Nature. 2014 Jun 26;510(7506):547-51. doi: 10.1038/nature13267. Epub 2014 May 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Amino Acids / pharmacology
  • Animals
  • Cell Cycle*
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Cyclin D1 / deficiency
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism*
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 4 / metabolism*
  • Diabetes Mellitus / metabolism
  • Enzyme Activation
  • Fasting
  • Gene Deletion
  • Gluconeogenesis / genetics
  • Glucose / metabolism*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Hepatocytes / cytology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Histone Acetyltransferases / metabolism
  • Homeostasis
  • Humans
  • Hyperglycemia / metabolism
  • Hyperinsulinism / metabolism
  • Insulin / metabolism*
  • Male
  • Mice
  • Phosphorylation
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • Signal Transduction*
  • Transcription Factors / metabolism
  • Transcription, Genetic / drug effects

Substances

  • Amino Acids
  • Insulin
  • RNA, Messenger
  • Transcription Factors
  • peroxisome-proliferator-activated receptor-gamma coactivator-1
  • Cyclin D1
  • GCN5 histone acetyltransferase, mouse
  • Histone Acetyltransferases
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Cdk4 protein, mouse
  • Cyclin-Dependent Kinase 4
  • Glycogen Synthase Kinase 3
  • Glucose