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J. Biol. Chem., Vol. 281, Issue 25, 17466-17473, June 23, 2006

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Repletion of Atypical Protein Kinase C following RNA Interference-mediated Depletion Restores Insulin-stimulated Glucose Transport^*

From the James A. Haley Veterans Medical Center and Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida 33612

The role of atypical protein kinase C (aPKC) in insulin-stimulated glucose transport in myocytes and adipocytes is controversial. Whereas studies involving the use of adenovirally mediated expression of kinase-inactive aPKC in L6 myocytes and 3T3/L1 and human adipocytes, and data from knock-out of aPKC in adipocytes derived from mouse embryonic stem cells and subsequently derived adipocytes, suggest that aPKCs are required for insulin-stimulated glucose transport, recent findings in studies of aPKC knockdown by small interfering RNA (RNAi) in 3T3/L1 adipocytes are conflicting. Moreover, there are no reports of aPKC knockdown in myocytes, wherein insulin effects on glucose transport are particularly relevant for understanding whole body glucose disposal. Presently, we exploited the fact that L6 myotubes and 3T3/L1 adipocytes have substantially different (30% nonhomology) major aPKCs, viz. PKC- in L6 myotubes and PKC- in 3T3/L1 adipocytes, that nevertheless can function interchangeably for glucose transport. Accordingly, in L6 myotubes, RNAi-targeting PKC-, but not PKC-, markedly depleted aPKC and concomitantly inhibited insulin-stimulated glucose transport; more importantly, these depleting/inhibitory effects were rescued by adenovirally mediated expression of PKC-. Conversely, in 3T3/L1 adipocytes, RNAi constructs targeting PKC-, but not PKC-, markedly depleted aPKC and concomitantly inhibited insulin-stimulated glucose transport; here again, these depleting/inhibitory effects were rescued by adenovirally mediated expression of PKC-. These findings in knockdown and, more convincingly, rescue studies, strongly support the hypothesis that aPKCs are required for insulin-stimulated glucose transport in myocytes and adipocytes.

Received for publication, October 4, 2005 , and in revised form, March 1, 2006.

^* This work was supported by funds from the Veterans Administration Merit Review Program and by National Institutes of Health Grant 2RO1-DK-38079-09A1. 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: ACOS-151, Research Service, James A. Haley Veterans Medical Center, and Dept. of Internal Medicine, University of South Florida College of Medicine, 13000 Bruce B. Downs Blvd., Tampa, Fl 33612. Tel.: 813-972-7662; Fax: 813-972-7662; E-mail: rfarese{at}hsc.usf.edu.

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