Xiaoqing Tang, Adilson Guilherme, Abhijit Chakladar, Aimee M Powelka, Silvana Konda, Joseph V Virbasius, Sarah M C Nicoloro, Juerg Straubhaar, Michael P Czech
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Proceedings of the National Academy of Sciences of the United States of America 2006 Feb 14The insulin-regulated glucose transporter GLUT4 is a key modulator of whole body glucose homeostasis, and its selective loss in adipose tissue or skeletal muscle causes insulin resistance and diabetes. Here we report an RNA interference-based screen of protein kinases expressed in adipocytes and identify four negative regulators of insulin-responsive glucose transport: the protein kinases PCTAIRE-1 (PCTK1), PFTAIRE-1 (PFTK1), IkappaB kinase alpha, and MAP4K4/NIK. Integrin-linked protein kinase was identified as a positive regulator of this process. We characterized one of these hits, MAP4K4/NIK, and found that it is unique among mitogen-activated protein (MAP) kinases expressed in cultured adipocytes in attenuating hexose transport. Remarkably, MAP4K4/NIK suppresses expression of the adipogenic transcription factors C/EBPalpha, C/EBPbeta, and PPARgamma and of GLUT4 itself in these cells. RNA interference-mediated depletion of MAP4K4/NIK early in differentiation enhances adipogenesis and triglyceride deposition, and even in fully differentiated adipocytes its loss up-regulates GLUT4. Conversely, conditions that inhibit adipogenesis such as TNF-alpha treatment or depletion of PPARgamma markedly up-regulate MAP4K4/NIK expression in cultured adipocytes. Furthermore, TNF-alpha signaling to down-regulate GLUT4 is impaired in the absence of MAP4K4/NIK, indicating that MAP4K4 expression is required for optimal TNF-alpha action. These results reveal a MAP4K4/NIK-dependent signaling pathway that potently inhibits PPARgamma-responsive gene expression, adipogenesis, and insulin-stimulated glucose transport.
Xiaoqing Tang, Adilson Guilherme, Abhijit Chakladar, Aimee M Powelka, Silvana Konda, Joseph V Virbasius, Sarah M C Nicoloro, Juerg Straubhaar, Michael P Czech. An RNA interference-based screen identifies MAP4K4/NIK as a negative regulator of PPARgamma, adipogenesis, and insulin-responsive hexose transport. Proceedings of the National Academy of Sciences of the United States of America. 2006 Feb 14;103(7):2087-92
PMID: 16461467
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