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

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.