Defective leptin/leptin receptor signaling improves regulatory T cell immune response and protects mice from atherosclerosis

Abstract

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)-γ 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. © 2007 American Heart Association, Inc.