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

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 a more minor role. Altogether we introduce a novel compound that 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.

journal_name

Endocrinology

journal_title

Endocrinology

authors

Elinav E,Niv-Spector L,Katz M,Price TO,Ali M,Yacobovitz M,Solomon G,Reicher S,Lynch JL,Halpern Z,Banks WA,Gertler A

doi

10.1210/en.2008-1706

subject

Has Abstract

pub_date

2009-07-01 00:00:00

pages

3083-91

issue

7

eissn

0013-7227

issn

1945-7170

pii

en.2008-1706

journal_volume

150

pub_type

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