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Brown Adipocyte-Specific PPAR&ggr; (Peroxisome Proliferator-Activated Receptor &ggr;) Deletion Impairs Perivascular Adipose Tissue Development and Enhances Atherosclerosis in Mice

Wenhao Xiong,Xiangjie Zhao,L. Villacorta,O. Rom,Minerva T. Garcia-Barrio,Yanhong Guo,Yanbo Fan,Tianqing Zhu,Jifeng Zhang,R. Zeng,Y. E. Chen,Zhisheng Jiang,Lin Chang

Published 2018 in Arteriosclerosis, Thrombosis and Vascular Biology

ABSTRACT

Objective— Perivascular adipose tissue (PVAT) contributes to vascular homeostasis by producing paracrine factors. Previously, we reported that selective deletion of PPAR&ggr; (peroxisome proliferator-activated receptor &ggr;) in vascular smooth muscle cells resulted in concurrent loss of PVAT and enhanced atherosclerosis in mice. To address the causal relationship between loss of PVAT and atherosclerosis, we used BA-PPAR&ggr;-KO (brown adipocyte-specific PPAR&ggr; knockout) mice. Approach and Results— Deletion of PPAR&ggr; in brown adipocytes did not affect PPAR&ggr; in white adipocytes or vascular smooth muscle cells or PPAR&agr; and PPAR&dgr; expression in brown adipocytes. However, development of PVAT and interscapular brown adipose tissue was remarkably impaired, associated with reduced expression of genes encoding lipogenic enzymes in the BA-PPAR&ggr;-KO mice. Thermogenesis in brown adipose tissue was significantly impaired with reduced expression of thermogenesis genes in brown adipose tissue and compensatory increase in subcutaneous and gonadal white adipose tissues. Remarkably, basal expression of inflammatory genes and macrophage infiltration in PVAT and brown adipose tissue were significantly increased in the BA-PPAR&ggr;-KO mice. BA-PPAR&ggr;-KO mice were crossbred with ApoE KO (apolipoprotein E knockout) mice to investigate the development of atherosclerosis. Flow cytometry analysis confirmed increased systemic and PVAT inflammation. Consequently, atherosclerotic lesions were significantly increased in mice with impaired PVAT development, thus indicating that the lack of normal PVAT is sufficient to drive increased atherosclerosis. Conclusions— PPAR&ggr; is required for functional PVAT development. PPAR&ggr; deficiency in PVAT, while still expressed in vascular smooth muscle cell, enhances atherosclerosis and results in vascular and systemic inflammation, providing new insights on the specific roles of PVAT in atherosclerosis and cardiovascular disease at large.

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