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J. Biol. Chem., Vol. 283, Issue 3, 1754-1763, January 18, 2008

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Leptin-mediated Cell Survival Signaling in Hippocampal Neurons Mediated by JAK STAT3 and Mitochondrial Stabilization^*

Zhihong Guo, Haiyang Jiang, Xiangru Xu, Wenzhen Duan, and Mark P. Mattson¹

From the Laboratory of Neurosciences and National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224 and the Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Leptin plays a pivotal role in the regulation of energy homeostasis and metabolism, primarily by acting on neurons in the hypothalamus that control food intake. However, leptin receptors are more widely expressed in the brain suggesting additional, as yet unknown, functions of leptin. Here we show that both embryonic and adult hippocampal neurons express leptin receptors coupled to activation of STAT3 and phosphatidylinositol 3-kinase-Akt signaling pathways. Leptin protects hippocampal neurons against cell death induced by neurotrophic factor withdrawal and excitotoxic and oxidative insults. The neuroprotective effect of leptin is antagonized by the JAK2-STAT3 inhibitor AG-490, STAT3 decoy DNA, and phosphatidylinositol 3-kinase/Akt inhibitors but not by an inhibitor of MAPK. Leptin induces the production of manganese superoxide dismutase and the anti-apoptotic protein Bcl-xL, and stabilizes mitochondrial membrane potential and lessens mitochondrial oxidative stress. Leptin receptor-deficient mice (db/db mice) are more vulnerable to seizure-induced hippocampal damage, and intraventricular administration of leptin protects neurons against seizures. By enhancing mitochondrial resistance to apoptosis and excitotoxicity, our findings suggest that leptin signaling serves a neurotrophic function in the developing and adult hippocampus.

Received for publication, May 7, 2007 , and in revised form, November 6, 2007.

^* This work was supported by the Intramural Research Program of the National Institute on Aging. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-3.

¹ To whom correspondence should be addressed. Tel.: 410-558-8463; Fax: 410-558-8465; E-mail: mattsonm{at}grc.nia.nih.gov.

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