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J. Biol. Chem., Vol. 282, Issue 11, 7783-7789, March 16, 2007

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MAP4K4 Gene Silencing in Human Skeletal Muscle Prevents Tumor Necrosis Factor--induced Insulin Resistance^*

From the Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, S-171 77 Stockholm, Sweden

Tumor necrosis factor- (TNF-) induces skeletal muscle insulin resistance by impairing insulin signaling events involved in GLUT4 translocation. We tested whether mitogenic-activated protein kinase kinase kinase kinase isoform 4 (MAP4K4) causes the TNF--induced negative regulation of extracellular signal-regulated kinase-1/2 (ERK-1/2), c-Jun NH₂-terminal kinase (JNK), and the insulin receptor substrate-1 (IRS-1) on the insulin signaling pathway governing glucose metabolism. Using small interfering RNA (siRNA) to suppress the expression of MAP4K4 protein 85% in primary human skeletal muscle cells, we provide evidence that TNF--induced insulin resistance on glucose uptake was completely prevented. MAP4K4 silencing inhibited TNF--induced negative signaling inputs by preventing excessive JNK and ERK-1/2 phosphorylation, as well as IRS-1 serine phosphorylation. These results highlight the MAPK4K4/JNK/ERK/IRS module in the negative regulation of insulin signaling to glucose transport in response to TNF-. Depletion of MAP4K4 also prevented TNF--induced insulin resistance on Akt and the Akt substrate 160 (AS160), providing evidence that appropriate insulin signaling inputs for glucose metabolism were rescued. Silencing of MAP2K1 and MAP2K4, signaling proteins downstream of MAP4K4, recapitulated the effect of MAP4K4 siRNA in TNF--treated cells. Thus, strategies to inhibit MAP4K4 may be efficacious in the prevention of TNF--induced inhibitory signals that cause skeletal muscle insulin resistance on glucose metabolism in humans. Moreover, in myotubes from insulin-resistant type II diabetic patients, siRNA against MAP4K4, MAP2K4, or MAP2K1 restored insulin action on glucose uptake to levels observed in healthy subjects. Collectively, our results demonstrate that MAP4K4 silencing prevents insulin resistance in human skeletal muscle and restores appropriate signaling inputs to enhance glucose uptake.

Received for publication, September 6, 2006 , and in revised form, January 11, 2007.

^* This work was supported by grants from the Swedish Research Council, the Swedish Diabetes Association, the Swedish Center for Sports Research, the Foundation for Scientific Studies of Diabetology, the Strategic Research Foundation (INGVAR II), and the Commission of the European Communities (Contract Number LSHM-CT-2004-005272 EXGENESIS, Contract Number LSHM-CT-2004-512013 EUGENEHEART, and Contract Number LSHM-CT-2004-512013 EUGENE2). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Karolinska Institutet, Dept. of Molecular Medicine and Surgery, Section of Integrative Physiology, von Eulers väg 4, 4th Fl., S-171 77 Stockholm, Sweden. Tel.: 46-8-524-875-80; Fax: 46-8-33-54-36; E-mail: Juleen.Zierath{at}ki.se.

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