RT Journal Article
T1 CDK4 is an essential insulin effector in adipocytes.
A1 Lagarrigue, Sylviane
A1 Lopez-Mejia, Isabel C
A1 Denechaud, Pierre-Damien
A1 Escoté, Xavier
A1 Castillo-Armengol, Judit
A1 Jimenez, Veronica
A1 Chavey, Carine
A1 Giralt, Albert
A1 Lai, Qiuwen
A1 Zhang, Lianjun
A1 Martinez-Carreres, Laia
A1 Delacuisine, Brigitte
A1 Annicotte, Jean-Sébastien
A1 Blanchet, Emilie
A1 Huré, Sébastien
A1 Abella, Anna
A1 Tinahones, Francisco J
A1 Vendrell, Joan
A1 Dubus, Pierre
A1 Bosch, Fatima
A1 Kahn, C Ronald
A1 Fajas, Lluis
AB 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.
YR 2015
FD 2015-12-14
LK http://hdl.handle.net/10668/9660
UL http://hdl.handle.net/10668/9660
LA en
DS RISalud
RD Apr 12, 2025