Objective— Peroxisome proliferator-activated receptor gamma (PPARγ) is highly expressed in macrophage-derived foam cells of atherosclerotic lesions, and its expression may have a dramatic impact on atherosclerosis.

Methods and Results— To investigate the contribution of macrophage PPARγ expression on atherogenesis in vivo, we generated macrophage-specific PPARγ knockout (MacPPARγKO) mice. C57BL/6 and low-density lipoprotein (LDL) receptor–deficient (LDLR^−/−) mice were reconstituted with MacPPARγKO or wild-type marrow and challenged with an atherogenic diet. No differences were found in serum lipids between recipients reconstituted with MacPPARγKO and wild-type marrow. In contrast, both C57BL/6 and LDLR^−/− mice transplanted with MacPPARγKO marrow had significantly larger atherosclerotic lesions than control recipients. In addition, MacPPARγKO→LDLR^−/− mice had higher numbers of macrophages in atherosclerotic lesions compared with controls. Peritoneal macrophages isolated from the MacPPARγKO mice had decreased uptake of oxidized but not acetylated LDL and showed no changes in either cholesterol efflux or inflammatory cytokine expression. Macrophages from MacPPARγKO mice had increased levels of migration and CC chemokine receptor 2 (CCR2) expression compared with wild-type macrophages.

Conclusion— Thus, macrophage PPARγ deficiency increases atherosclerosis under conditions of mild and severe hypercholesterolemia, indicating an antiatherogenic role for PPARγ, which may be caused, at least in part, by modulation of CCR2 expression and monocyte recruitment.