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

Nature
Authors
Keywords
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.

Year of Publication
2014
Journal
Nature
Volume
510
Issue
7506
Pages
547-51
Date Published
2014 Jun 26
ISSN
1476-4687
URL
DOI
10.1038/nature13267
PubMed ID
24870244
PubMed Central ID
PMC4076706
Links
Grant list
R01 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