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J. Biol. Chem., Vol. 279, Issue 48, 49704-49715, November 26, 2004

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Melanocortin-independent Effects of Leptin on Hepatic Glucose Fluxes^*

Roger Gutiérrez-Juárez, Silvana Obici, and Luciano Rossetti

From the Departments of Medicine & Molecular Pharmacology, Diabetes Research & Training Center, Albert Einstein College of Medicine, Bronx, New York, 10461

Leptin and insulin share some hypothalamic signaling molecules, but their central administration induces different effects on hepatic glucose fluxes. Acute insulin infusion in the third cerebral ventricle inhibits endogenous glucose production (GP), whereas acute leptin infusion stimulates gluconeogenesis but does not alter GP because of a compensatory decrease in glycogenolysis. Because melanocortin agonists also stimulate hepatic gluconeogenesis, here we examined whether central melanocortin blockade modifies the acute effects of leptin on GP, on gluconeogenesis, on glycogenolysis, and/or on the hepatic expression of the gluconeogenic enzymes glucose-6-phosphatase (Glc-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK). Systemic or central administration of leptin alone did not alter GP, despite increasing both the rate of gluconeogenesis and the expression of Glc-6-Pase and PEPCK. When activation of the central melanocortin pathway was prevented, the effects of leptin on gluconeogenesis, Glc-6-Pase, and PEPCK were abolished, and a marked suppression of glycogenolysis resulted in decreased GP. We conclude that leptin regulates hepatic glucose fluxes through a melanocortin-dependent pathway leading to stimulation of gluconeogenesis and a melanocortin-independent pathway causing inhibition of GP and glycogenolysis.

Received for publication, July 30, 2004 , and in revised form, September 9, 2004.

^* This work was supported in part by National Institutes of Health Grants DK 48321 and DK 45024 (to L. R.) and funds from the American Diabetes Association (to S. O. and L. R.). 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.

Recipient of a mentor-based fellowship from the American Diabetes Association.

To whom correspondence should be addressed: Depts. of Medicine & Molecular Pharmacology, Diabetes Research & Training Center, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Tel.: 718-430-4118/4215; Fax: 718-430-8557; E-mail: rossetti{at}aecom.yu.edu.

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