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J. Biol. Chem., Vol. 281, Issue 40, 29719-29729, October 6, 2006

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Effect of TRB3 on Insulin and Nutrient-stimulated Hepatic p70 S6 Kinase Activity^*

Rie Matsushima¹, Nagakatsu Harada, Nicholas J. G. Webster^¶, Yasuo M. Tsutsumi^¶, and Yutaka Nakaya

From the Department of Nutrition and Metabolism, Institute of Health Biosciences, the University of Tokushima Graduate School, Tokushima City 770-8503, Japan, the Department of Medicine, University of California San Diego, La Jolla, California 92093, and the ^¶Medical Research Service, Veterans Affairs San Diego Healthcare System, San Diego, California 92161

Insulin and nutrients activate hepatic p70 S6 kinase (S6K1) to regulate protein synthesis. Paradoxically, activation of S6K1 also leads to the development of insulin resistance. In this study, we investigated the effect of TRB3, which acts as an endogenous inhibitor of Akt, on S6K1 activity in vitro and in vivo. In cultured cells, overexpression of TRB3 completely inhibited insulin-stimulated S6K1 activation by mammalian target of rapamycin, whereas knockdown of endogenous TRB3 increased both basal and insulin-stimulated activity. In C57BL/6 mice, adenoviral overexpression of TRB3 inhibited insulin-stimulated activation of hepatic S6K1. In contrast, overexpression of TRB3 did not inhibit nutrient-stimulated S6K1 activity. We also investigated the effect of starvation, feeding, or insulin treatment on TRB3 levels and S6K1 activity in the liver of C57BL/6 and db/db mice. Both insulin and feeding activate S6K1 in db/db mice, but only insulin activates in the C57BL/6 strain. TRB3 levels were 3.5-fold higher in db/db mice than C57BL/6 mice and were unresponsive to feeding or insulin, whereas both treatments reduced TRB3 in C57BL/6 mice. Akt was activated by insulin alone in the C57BL/6 strain and but not in db/db mice. Both insulin and feeding activated mammalian target of rapamycin similarly in these mice; however, feeding was unable to activate the downstream target S6K1 in C57BL/6 mice. These results suggest that the nutrient excess in the hyperphagic, hyperinsulinemic db/db mouse primes the hepatocyte to respond to nutrients resulting in elevated S6K1 activity. The combination of elevated TRB3 and constitutive S6K1 activity results in decreased insulin signaling via the IRS-1/phosphatidylinositol 3-kinase/Akt pathway.

Received for publication, October 27, 2005 , and in revised form, July 31, 2006.

^* 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: Dept. of Nutrition and Metabolism, Institute of Health Biosciences, the University of Tokushima Graduate School, 3-18-15, Kuramoto-cho, Tokushima City 770-8503, Japan. Tel.: 81-88-633-9249; Fax: 81-88-633-7113; E-mail: amocoerie{at}sbcglobal.net.

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