PMID:26657864

Citation	Lagarrigue, S, Lopez-Mejia, IC, Denechaud, PD, Escoté, X, Castillo-Armengol, J, Jimenez, V, Chavey, C, Giralt, A, Lai, Q, Zhang, L, Martinez-Carreres, L, Delacuisine, B, Annicotte, JS, Blanchet, E, Huré, S, Abella, A, Tinahones, FJ, Vendrell, J, Dubus, P, Bosch, F, Kahn, CR and Fajas, L (2016) CDK4 is an essential insulin effector in adipocytes. J. Clin. Invest. 126:335-48
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.
Links	PubMed PMC4701556 Online version:10.1172/JCI81480
Keywords	3T3-L1 Cells; Adipocytes/metabolism; Adipose Tissue, White/metabolism; Animals; Cyclin D3/physiology; Cyclin-Dependent Kinase 4/antagonists & inhibitors; Cyclin-Dependent Kinase 4/physiology; E2F1 Transcription Factor/physiology; Female; Humans; Insulin/pharmacology; Insulin Receptor Substrate Proteins/metabolism; Insulin Resistance; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Phosphorylation; Signal Transduction
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:LMNA	part_of	GO:0005634: nucleus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:P85A	part_of	GO:0032991: protein-containing complex	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:P85A	acts_upstream_of_or_within	GO:0032869: cellular response to insulin stimulus	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:P85A	acts_upstream_of_or_within	GO:0046626: regulation of insulin receptor signaling pathway	ECO:0000316: genetic interaction evidence used in manual assertion	MGI:MGI:88315	P		Seeded From UniProt	complete

References

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