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J. Biol. Chem., Vol. 283, Issue 33, 22505-22512, August 15, 2008

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Neuropoietin Attenuates Adipogenesis and Induces Insulin Resistance in Adipocytes^*

Ursula A. White, William C. Stewart, Randall L. Mynatt^¶, and Jacqueline M. Stephens¹

From the Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803, the Middle Tennessee State University, Murfreesboro, Tennessee 37132, and the ^¶Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808

Recent findings have implicated gp130 receptor ligands, particularly ciliary neurotrophic factor (CNTF), as potential anti-obesity therapeutics. Neuropoietin (NP) is a recently discovered cytokine in the gp130 family that shares functional and structural features with CNTF and signals via the CNTF receptor tripartite complex comprised of CNTFR, LIF receptor, and gp130. NP plays a role in the development of the nervous system, but the effects of NP on adipocytes have not been previously examined. Because CNTF exerts anti-obesogenic effects in adipocytes and NP shares the same receptor complex, we investigated the effects of NP on adipocyte development and insulin action. Using cultured 3T3-L1 adipocytes, we observed that NP has the ability to block adipogenesis in a dose- and time-dependent manner. We also observed that cultured adipocytes, as well as murine adipose tissue, are highly responsive to acute NP treatment. Rodents injected with NP had a substantial increase in STAT3 tyrosine phosphorylation and ERK 1 and 2 activation. We also observed the induction of SOCS-3 mRNA in 3T3-L1 adipocytes following NP treatment. Unlike CNTF, our studies have revealed that NP also substantially attenuates insulin-stimulated glucose uptake in 3T3-L1 adipocytes. In addition, NP blocks insulin action in adipose tissue in vivo. These observations are supported by data demonstrating that NP impairs insulin signaling via decreased activation of both IRS-1 and Akt. In summary, we have observed that both adipocytes in vitro and in vivo are highly responsive to NP, and this cytokine has the ability to affect insulin signaling in fat cells. These novel observations suggest that NP, unlike CNTF, may not be a viable obesity therapeutic.

Received for publication, December 22, 2007 , and in revised form, May 14, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant R01DK52968 (to J. M. S.). 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. Tel.: 225-578-1749; Fax: 225-578-2597; E-mail: jsteph1{at}lsu.edu.

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