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J. Biol. Chem., Vol. 282, Issue 31, 22765-22774, August 3, 2007

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Liver-specific Knockdown of JNK1 Up-regulates Proliferator-activated Receptor Coactivator 1 and Increases Plasma Triglyceride despite Reduced Glucose and Insulin Levels in Diet-induced Obese Mice^*

From the Department of Metabolic Disease Research, Abbott Laboratories, Abbott Park, Illinois 60064

The c-Jun N-terminal kinases (JNKs) have been implicated in the development of insulin resistance, diabetes, and obesity. Genetic disruption of JNK1, but not JNK2, improves insulin sensitivity in diet-induced obese (DIO) mice. We applied RNA interference to investigate the specific role of hepatic JNK1 in contributing to insulin resistance in DIO mice. Adenovirus-mediated delivery of JNK1 short-hairpin RNA (Ad-shJNK1) resulted in almost complete knockdown of hepatic JNK1 protein without affecting JNK1 protein in other tissues. Liver-specific knockdown of JNK1 resulted in significant reductions in circulating insulin and glucose levels, by 57 and 16%, respectively. At the molecular level, JNK1 knockdown mice had sustained and significant increase of hepatic Akt phosphorylation. Furthermore, knockdown of JNK1 enhanced insulin signaling in vitro. Unexpectedly, plasma triglyceride levels were robustly elevated upon hepatic JNK1 knockdown. Concomitantly, expression of proliferator-activated receptor coactivator 1, glucokinase, and microsomal triacylglycerol transfer protein was increased. Further gene expression analysis demonstrated that knockdown of JNK1 up-regulates the hepatic expression of clusters of genes in glycolysis and several genes in triglyceride synthesis pathways. Our results demonstrate that liver-specific knockdown of JNK1 lowers circulating glucose and insulin levels but increases triglyceride levels in DIO mice.

Received for publication, January 26, 2007 , and in revised form, June 1, 2007.

^* Conflict of interest: R. Yang, D. M. Wilcox, D. L. Haasch, P. M. Jung, P. T. Nguyen, M. J. Voorbach, S. Doktor, S. Brodjian, E. N. Bush, J. M. Trevillyan, C. A. Collins, P. B. Jacobson, C. M. Rondinone, and T. K. Surowy, are employees or potentially own stock and/or hold stock options in Abbott Laboratories. 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.

² Present address: University of Illinois at Chicago, Chicago, IL 60612.

³ Present address: Lilly Research Laboratories, Indianapolis, IN 46285.

⁴ Present address: Hoffmann-La Roche Inc., Metabolic Diseases, Nutley, NJ 07110.

¹ To whom correspondence should be addressed: Abbott Laboratories, Metabolic Disease Research, 100 Abbott Park Rd., Abbott Park, IL 60064. Tel.: 847-360-0327; Fax: 847-938-1674; E-mail: ruojingyang{at}yahoo.com.

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