Insulin constitutes a principal evolutionarily conserved hormonal axis for maintaining glucose homeostasis1,2,3; dysregulation of this axis causes diabetes2,4. PGC-1α (peroxisome-proliferator-activated receptor-γ coactivator-1α) links insulin signalling to the expression of glucose and lipid metabolic genes5,6,7. 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-1α8,9. Although insulin is a mitogenic signal in proliferative cells10,11, 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.
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We thank all the members of the Puigserver laboratory for discussions and suggestions about this project. We also appreciate the consultations with and efforts by M. Jedrychowski and S. Gygi for proteomic analysis. Y.L. was supported in part by a 21st Century Leaders scholarship from Ewha Womans University. J.E.D. was supported in part by a National Research Service Award Kirschstein Fellowship from the National Institutes of Health (NIH). The participating researchers were supported with funds from the Dana-Farber Cancer Institute and with grants from the American Diabetes Association, Department of Defense, NIH/National Institute of Diabetes and Digestive and Kidney Diseases (RO1069966 and R24DK080261-06), NIH (RO3 MH092174) awarded to P.P., NIH (RO1 CA108420) awarded to P.S. and NIH (DK059635) awarded to Yale’s Mouse Metabolic Phenotyping Center/G.I.S.
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Molecular Cancer (2019)