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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2691.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Defective Leptin/Leptin Receptor Signaling Improves Regulatory T Cell Immune Response and Protects Mice From Atherosclerosis

Soraya Taleb; Olivier Herbin; Hafid Ait-Oufella; Wim Verreth; Pierre Gourdy; Véronique Barateau; Régine Merval; Bruno Esposito; Karine Clément; Paul Holvoet; Alain Tedgui; Ziad Mallat

From the Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 689 (S.T., O.H., H.A.O., V.B., R.M., B.E., A.T., Z.M.), Centre de Recherche Cardiovasculaire Lariboisière, U589 (P.G.), Toulouse, and Unit U755 (K.C.), Paris, France; Atherosclerosis and Metabolism Unit (W.V., P.H.), Katholieke Universiteit Leuven, Leuven, Belgium; and Université Pierre et Marie Curie-Paris 6 (K.C.), Paris, France.

Correspondence to Ziad Mallat, MD, PhD, Institut National de la Sante et de la Recherche Medicale (Inserm), U689, 41 Bd de la Chapelle, Paris, France 75010. E-mail mallat{at}larib.inserm.fr

Objective— Obesity is a major risk factor for atherosclerosis and is associated with increased cardiovascular morbidity and mortality. However, the precise molecular pathways responsible for this close association remain poorly understood.

Methods and Results— In this study, we report that leptin-deficiency (ob/ob) in low-density lipoprotein receptor knockout (ldlr^–/–) mice induces an unexpected 2.2- to 6-fold reduction in atherosclerotic lesion development, compared with ldlr^–/– mice having similar total cholesterol levels. Ldlr^–/–/ob/ob mice show reduced T cell helper type 1 (Th1) response, enhanced expression of Foxp3, the specification transcription factor of regulatory T (Treg) cells, and improved Treg cell function. Leptin receptor-deficient (db/db) mice display marked increase in the number and suppressive function of Treg cells. Supplementation of Treg-deficient lymphocytes with Treg cells from db/db mice in an experimental model of atherosclerosis induces a significant reduction of lesion size and a marked inhibition of interferon (INF)- production, compared with supplementation by Treg cells from wild-type mice.

Conclusions— These results identify a critical role for leptin/leptin receptor pathway in the modulation of the regulatory immune response in atherosclerosis, and suggest that alteration in regulatory immunity may predispose obese individuals to atherosclerosis.

Leptin, a hormone that increases with obesity, was suggested to either accelerate or protect from atherosclerosis. Here, we identify a critical role for leptin/leptin receptor pathway in the modulation of the regulatory immune response in atherosclerosis, and suggest that alteration in regulatory immunity may predispose obese individuals to atherosclerosis.

Key Words: leptin • obesity • metabolic syndrome • atherosclerosis • immunity

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