Journal Article

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

Sicinski, Piotr, Lee, Yoonjin, Lim, Ji-Hong, Puigserver, Pere, Ruan, Hai-Bin, Chim, Helen, Shulman, Gerald I., Yang, Xiaoyong, Vazquez, Francisca, Jurczak, Michael, Dominy, John E., Choi, Yoon Jong, Tolliday, Nicola, Camporez, Joao Paulo

2014

Overview

Formation of an active cyclin D1–Cdk4 complex suppresses glucose metabolism independently of cell division. Cell-cycle components reused in insulin signalling The mechanisms connecting insulin signalling and transcriptionally mediated suppression of gluconeogenic genes remain unclear. This study of insulin signalling in mice supports a regulatory model in which insulin facilitates the formation of an active cyclin D1–Cdk4 complex that subsequently suppresses gluconeogenesis, in part by decreasing PGC-1 activity through GCN5-mediated acetylation. Thus, insulin uses components of the cell-cycle machinery to control glucose homeostasis independently of cell division. Further studies of the metabolic functions of cell-cycle components in different tissues could provide candidate targets for drugs to treat metabolic diseases. Insulin constitutes a principal evolutionarily conserved hormonal axis for maintaining glucose homeostasis 1 , 2 , 3 ; dysregulation of this axis causes diabetes 2 , 4 . PGC-1α (peroxisome-proliferator-activated receptor-γ coactivator-1α) links insulin signalling to the expression of glucose and lipid metabolic genes 5 , 6 , 7 . 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 8 , 9 . Although insulin is a mitogenic signal in proliferative cells 10 , 11 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 38 / 631/443/319 / 82 / 96 / Acetylation / Amino acids / Amino Acids - pharmacology / Analysis / Animals / Cell Cycle / Cell Line, Tumor / Cell Nucleus - metabolism / Cells, Cultured / Cyclin D proteins / 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 / Glucose - metabolism / Glycogen Synthase Kinase 3 - metabolism / Glycogen Synthase Kinase 3 beta / Hepatocytes - cytology / Hepatocytes - drug effects / Hepatocytes - metabolism / Histone Acetyltransferases - metabolism / Homeostasis / Humanities and Social Sciences / Humans / Hyperglycemia - metabolism / Hyperinsulinism - metabolism / Insulin / Insulin - metabolism / Kinases / letter / Male / Metabolic disorders / Mice / multidisciplinary / Phosphorylation / Physiological aspects / RNA, Messenger - analysis / RNA, Messenger - genetics / Rodents / Science / Signal Transduction / Transcription Factors - metabolism / Transcription, Genetic - drug effects