You are here

Nature DOI:10.1038/nature13267

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

Publication TypeJournal Article
Year of Publication2014
AuthorsLee, Y, Dominy, JE, Choi, YJong, Jurczak, M, Tolliday, N, Camporez, JPaulo, Chim, H, Lim, J-H, Bin Ruan, H-, Yang, X, Vazquez, F, Sicinski, P, Shulman, GI, Puigserver, P
JournalNature
Volume510
Issue7506
Pages547-51
Date Published2014 Jun 26
ISSN1476-4687
KeywordsAcetylation, Amino Acids, Animals, Cell Cycle, Cell Line, Tumor, Cell Nucleus, Cells, Cultured, Cyclin D1, Cyclin-Dependent Kinase 4, Diabetes Mellitus, Enzyme Activation, Fasting, Gene Deletion, Gluconeogenesis, Glucose, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Hepatocytes, Histone Acetyltransferases, Homeostasis, Humans, Hyperglycemia, Hyperinsulinism, Insulin, Male, Mice, Phosphorylation, RNA, Messenger, Signal Transduction, Transcription Factors, Transcription, Genetic
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.

URLhttp://dx.doi.org/10.1038/nature13267
DOI10.1038/nature13267
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24870244?dopt=Abstract

Alternate JournalNature
PubMed ID24870244
PubMed Central IDPMC4076706
Grant ListR01 CA083688 / CA / NCI NIH HHS / United States
R01 DK089098 / DK / NIDDK NIH HHS / United States
R03 MH092174 / MH / NIMH NIH HHS / United States
R03 DA032468 / DA / NIDA NIH HHS / United States
F32 DK083871 / DK / NIDDK NIH HHS / United States
U24 DK059635 / DK / NIDDK NIH HHS / United States
R24 DK080261 / DK / NIDDK NIH HHS / United States
R01 CA108420 / CA / NCI NIH HHS / United States
DK059635 / DK / NIDDK NIH HHS / United States
P30 DK034989 / DK / NIDDK NIH HHS / United States
R24DK080261-06 / DK / NIDDK NIH HHS / United States
R01 DK069966 / DK / NIDDK NIH HHS / United States
R01069966 / / PHS HHS / United States