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Mice with adipocyte-specific inactivation of low-density lipoprotein receptor–related protein-1 (LRP1) are resistant to diet-induced obesity and hyperglycemia because of compensatory thermogenic response by muscle. However, the physiological function of LRP1 in mature adipocytes and its role in cardiovascular disease modulation are unknown. This study compared perivascular adipose tissues (PVAT) from wild-type (adLrp1+/+) and adipocyte-specific LRP1 knockout (adLrp1−/−) mice in modulation of atherosclerosis progression.Analysis of adipose tissues from adLrp1+/+ and adLrp1−/− mice after Western diet feeding for 16 weeks revealed that, in comparison to adLrp1+/+ mice, the adipocytes in adLrp1−/− mice were smaller, but their adipose tissues were more inflamed with increased monocyte–macrophage infiltration and inflammatory gene expression. The transplantation of PVAT from chow-fed adLrp1+/+ and adLrp1−/− mice into the area surrounding the carotid arteries of Ldlr−/− mice before feeding the Western diet revealed a contributory role of PVAT toward hypercholesterolemia-induced atherosclerosis. Importantly, recipients of adLrp1−/− PVAT displayed a 3-fold increase in atherosclerosis compared with adLrp1+/+ PVAT recipients. The increased atherosclerosis invoked by LRP1-deficient PVAT was associated with elevated monocyte–macrophage infiltration and inflammatory cytokine expression in the transplanted fat.PVAT provide outside-in signals through the adventitia to modulate atherosclerotic lesion progression in response to hypercholesterolemia. Moreover, adipocytes with LRP1 deficiency are dysfunctional and more inflamed. This latter observation adds the adipose tissue to the list of anatomic sites where LRP1 expression is important to protect against diet-induced atherosclerosis.