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Title: CDK4 is an essential insulin effector in adipocytes.
Authors: Lagarrigue, Sylviane
Lopez-Mejia, Isabel C
Denechaud, Pierre-Damien
Escoté, Xavier
Castillo-Armengol, Judit
Jimenez, Veronica
Chavey, Carine
Giralt, Albert
Lai, Qiuwen
Zhang, Lianjun
Martinez-Carreres, Laia
Delacuisine, Brigitte
Annicotte, Jean-Sébastien
Blanchet, Emilie
Huré, Sébastien
Abella, Anna
Tinahones, Francisco J
Vendrell, Joan
Dubus, Pierre
Bosch, Fatima
Kahn, C Ronald
Fajas, Lluis
metadata.dc.subject.mesh: 3T3-L1 Cells
Adipose Tissue, White
Cyclin D3
Cyclin-Dependent Kinase 4
E2F1 Transcription Factor
Insulin Receptor Substrate Proteins
Insulin Resistance
Lipid Metabolism
Mice, Inbred C57BL
Signal Transduction
Issue Date: 14-Dec-2015
Abstract: Insulin resistance is a fundamental pathogenic factor that characterizes various metabolic disorders, including obesity and type 2 diabetes. Adipose tissue contributes to the development of obesity-related insulin resistance through increased release of fatty acids, altered adipokine secretion, and/or macrophage infiltration and cytokine release. Here, we aimed to analyze the participation of the cyclin-dependent kinase 4 (CDK4) in adipose tissue biology. We determined that white adipose tissue (WAT) from CDK4-deficient mice exhibits impaired lipogenesis and increased lipolysis. Conversely, lipolysis was decreased and lipogenesis was increased in mice expressing a mutant hyperactive form of CDK4 (CDK4(R24C)). A global kinome analysis of CDK4-deficient mice following insulin stimulation revealed that insulin signaling is impaired in these animals. We determined that insulin activates the CCND3-CDK4 complex, which in turn phosphorylates insulin receptor substrate 2 (IRS2) at serine 388, thereby creating a positive feedback loop that maintains adipocyte insulin signaling. Furthermore, we found that CCND3 expression and IRS2 serine 388 phosphorylation are increased in human obese subjects. Together, our results demonstrate that CDK4 is a major regulator of insulin signaling in WAT.
metadata.dc.identifier.doi: 10.1172/JCI81480
Appears in Collections:Producción 2020

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