אסיף מאגר המחקר החקלאי

Pegylated leptin antagonist is a potent orexigenic agent: Preparation and mechanism of activity

Year:

2009

Source of publication :

Authors :

Volume :

150

Co-Authors:

Elinav, E., Institute for Gastroenterology and Liver Disease, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel
Niv-Spector, L., Institute of Biochemistry, Food Science, and Nutrition, Robert H. Smith Faculty of Agriculture, Food, and the Environment, Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel
Katz, M., Institute for Gastroenterology and Liver Disease, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel
Price, T.O., Geriatrics Research Education and Clinical Center, Veterans Affairs Medical Center-St. Louis, Saint Louis University School of Medicine, St. Louis, MO 63106, United States, Division of Geriatrics, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO 63106, United States
Ali, M., Institute for Gastroenterology and Liver Disease, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel
Yacobovitz, M., Institute of Biochemistry, Food Science, and Nutrition, Robert H. Smith Faculty of Agriculture, Food, and the Environment, Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel
Solomon, G., Institute of Biochemistry, Food Science, and Nutrition, Robert H. Smith Faculty of Agriculture, Food, and the Environment, Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel
Reicher, S., Institute of Biochemistry, Food Science, and Nutrition, Robert H. Smith Faculty of Agriculture, Food, and the Environment, Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel
Lynch, J.L., Geriatrics Research Education and Clinical Center, Veterans Affairs Medical Center-St. Louis, Saint Louis University School of Medicine, St. Louis, MO 63106, United States, Division of Geriatrics, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO 63106, United States
Halpern, Z., Institute for Gastroenterology and Liver Disease, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel
Banks, W.A., Geriatrics Research Education and Clinical Center, Veterans Affairs Medical Center-St. Louis, Saint Louis University School of Medicine, St. Louis, MO 63106, United States, Division of Geriatrics, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO 63106, United States
Gertler, A., Institute of Biochemistry, Food Science, and Nutrition, Robert H. Smith Faculty of Agriculture, Food, and the Environment, Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel

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Abstract:

Leptin, a pleiotropic adipokine, is a central regulator of appetite and weight and a key immunomodulatory protein. Although inborn leptin deficiency causes weight gain, it is unclear whether induced leptin deficiency in adult wild-type animals would be orexigenic. Previous work with a potent competitive leptin antagonist did not induce a true metabolic state of leptin deficiency in mice because of a short circulating half-life. In this study, we increased the half-life of the leptin antagonist by pegylation, which resulted in significantly increased bioavailability and retaining of antagonistic activity. Mice administered the pegylated antagonist showed a rapid and dramatic increase in food intake with weight gain. Resulting fat was confined to the mesenteric region with no accumulation in the liver. Serum cholesterol, triglyceride, and hepatic aminotransferases remained unaffected. Weight changes were reversible on cessation of leptin antagonist treatment. The mechanism of severe central leptin deficiency was found to be primarily caused by blockade of transport of circulating leptin across the blood-brain barrier with antagonisms at the arcuate nucleus playing amoreminor role. Altogetherweintroduce a novelcompoundthat induces central and peripheral leptin deficiency. This compound should be useful in exploring the involvement of leptin in metabolic and immune processes and could serve as a therapeutic for the treatment of cachexia. Copyright © 2009 by The Endocrine Society.

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