Editors' ChoiceMetabolism

Cycling Down Glucose Concentrations

Sci. Signal.  01 Jul 2014:
Vol. 7, Issue 332, pp. ec179
DOI: 10.1126/scisignal.2005641

Under fasting conditions, the liver produces glucose in a process called gluconeogenesis, through the induction of genes encoding gluconeogenic enzymes, such as phosphoenolpyruvate carboxykinase 1 (PCK1), in part through the transcriptional coactivator PGC-1α (peroxisome-proliferator–activated receptor-γ coactivator-1α). Food intake triggers the release of insulin, which suppresses the expression of these gluconeogenic genes. The activity of PGC-1α is suppressed by acetylation by acetyltransferases, such as GCN5 (general control nonrepressed protein 5). Lee et al. discovered that two different pharmacological inhibitors of cyclin-dependent kinase 4 (CDK4) or by CDK4 knockdown reduced GCN5-dependent acetylation of PGC-1α in U-2OS cells. CDK4 bound to and phosphorylated GCN5, activating the acetyltransferase. In primary hepatocytes overexpressing PGC-1α, glucose production and gluconeogenic gene expression were increased by pharmacological inhibition of CDK4 and decreased by expression of wild-type or the T286A mutant cyclin D1, both of which activate CDK4. The T286A mutant cannot be phosphorylated by glycogen synthase kinase 3β (GSK-3β) and is retained in the cytoplasm, where it undergoes proteasomal degradation. GSK-3β is inactivated by insulin signaling, and pharmacological inhibition of GSK-3β in hepatocytes increased the abundance of cyclin D1 in the nucleus (where it is not degraded), increased the acetylation of PGC-1α, and reduced the expression of gluconeogenic genes. In refed mice, Pck1 expression and glycemia were increased by pharmacological inhibition of CDK4 and decreased by adenoviral overexpression of the T286A form of cyclin D1 in the liver. Refeeding in mice increased the mRNA and protein abundance of cyclin D1 in the liver and the kinase activity of CDK4 without inducing cell division. When refed, mice with a liver-specific knockout of cyclin D1 showed greater induction of gluconeogenic gene expression, increased glycemia, and moderate insulin and glucose intolerance. The abundance of cyclin D1 was higher in fasted db/db mice, which are a model of diabetes, and in mice fed a high-fat diet. Hepatic overexpression of the T286A form of cyclin D1 reduced gluconeogenic gene expression, glycemia, and hepatic glucose production in db/db mice. Thus, in the liver, the cyclin D1-CDK4 complex does not promote cell cycle progression but rather is activated by insulin signaling to suppress gluconeogenesis and promote glucose homeostasis.

Y. Lee, J. E. Dominy, Y. J. Choi, M. Jurczak, N. Tolliday, J. P. Camporez, H. Chim, J.-H. Lim, H.-B. Ruan, X. Yang, F. Vazquez, P. Sicinski, G. I. Shulman, P. Puigserver, Cyclin D1–Cdk4 controls glucose metabolism independently of cell cycle progression. Nature 510, 547–551 (2014). [PubMed]