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.


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)-gamma 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.
Taleb
Soraya
S
Institut National de la Sante et de la Recherche Medicale, U689, 41 Bd de la Chapelle, Paris, France.
Herbin
Olivier
O
Ait-Oufella
Hafid
H
Verreth
Wim
W
Gourdy
Pierre
P
Barateau
Véronique
V
Merval
Régine
R
Esposito
Bruno
B
Clément
Karine
K
Holvoet
Paul
P
Tedgui
Alain
A
Mallat
Ziad
Z
D019264:Adoptive Transfer; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007111:Immunity, Cellular / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism; D020738:Leptin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000150:complications* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D054411:Receptors, Leptin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D018417:Th1 Cells / Q000378:metabolism*
D001057:Apolipoproteins E; D018106:CD28 Antigens; D004041:Dietary Fats; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020738:Leptin; D008055:Lipids; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D007371:Interferon-gamma