Publication Date:
2014-05-30
Description:
Insulin constitutes a principal evolutionarily conserved hormonal axis for maintaining glucose homeostasis; dysregulation of this axis causes diabetes. PGC-1alpha (peroxisome-proliferator-activated receptor-gamma coactivator-1alpha) links insulin signalling to the expression of glucose and lipid metabolic genes. The histone acetyltransferase GCN5 (general control non-repressed protein 5) acetylates PGC-1alpha and suppresses its transcriptional activity, whereas sirtuin 1 deacetylates and activates PGC-1alpha. 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-1alpha acetylation. Insulin/GSK-3beta (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-1alpha 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076706/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076706/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Yoonjin -- Dominy, John E -- Choi, Yoon Jong -- Jurczak, Michael -- Tolliday, Nicola -- Camporez, Joao Paulo -- Chim, Helen -- Lim, Ji-Hong -- Ruan, Hai-Bin -- Yang, Xiaoyong -- Vazquez, Francisca -- Sicinski, Piotr -- Shulman, Gerald I -- Puigserver, Pere -- DK059635/DK/NIDDK NIH HHS/ -- F32 DK083871/DK/NIDDK NIH HHS/ -- P30 DK034989/DK/NIDDK NIH HHS/ -- R01 CA083688/CA/NCI NIH HHS/ -- R01 CA108420/CA/NCI NIH HHS/ -- R01 DK069966/DK/NIDDK NIH HHS/ -- R01 DK089098/DK/NIDDK NIH HHS/ -- R01069966/PHS HHS/ -- R03 DA032468/DA/NIDA NIH HHS/ -- R03 MH092174/MH/NIMH NIH HHS/ -- R24 DK080261/DK/NIDDK NIH HHS/ -- R24DK080261-06/DK/NIDDK NIH HHS/ -- U24 DK059635/DK/NIDDK NIH HHS/ -- England -- Nature. 2014 Jun 26;510(7506):547-51. doi: 10.1038/nature13267. Epub 2014 May 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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. ; 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. ; 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 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. ; Chemical Biology Platform, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02141, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24870244" target="_blank"〉PubMed〈/a〉
Keywords:
Acetylation
;
Amino Acids/pharmacology
;
Animals
;
*Cell Cycle
;
Cell Line, Tumor
;
Cell Nucleus/metabolism
;
Cells, Cultured
;
Cyclin D1/deficiency/genetics/*metabolism
;
Cyclin-Dependent Kinase 4/antagonists & inhibitors/*metabolism
;
Diabetes Mellitus/metabolism
;
Enzyme Activation
;
Fasting
;
Gene Deletion
;
Gluconeogenesis/genetics
;
Glucose/*metabolism
;
Glycogen Synthase Kinase 3/metabolism
;
Hepatocytes/cytology/drug effects/metabolism
;
Histone Acetyltransferases/metabolism
;
Homeostasis
;
Humans
;
Hyperglycemia/metabolism
;
Hyperinsulinism/metabolism
;
Insulin/*metabolism
;
Male
;
Mice
;
Phosphorylation
;
RNA, Messenger/analysis/genetics
;
*Signal Transduction
;
Transcription Factors/metabolism
;
Transcription, Genetic/drug effects
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
