The beta-3 adrenoceptor (β3-AR) protects against the progression of atherosclerosis. However, the specific mechanism of this antiatherosclerotic effect is still not clear. Thus, the aim of this study was to understand the antiatherosclerotic effects of β3-AR. Thirty-six male homozygous apolipoprotein E-deficient mice and wild-type C57BL/6J mice were randomized into 6 treatment groups: wild-type, atherosclerotic model, atorvastatin, low-dose β3-AR agonist, high-dose β3-AR agonist, and β3-AR antagonist groups. The serum lipids, aortic-free cholesterol (FC), and cholesteryl ester (CE) concentrations were measured at the end of the treatments. The mRNA expression levels of liver apolipoprotein A-I (apoA-I), peroxisome proliferator-activated receptor-α (PPARa), and peroxisome proliferator-activated receptor-γ (PPARγ) were detected by quantitative real-time PCR. Protein expression levels of apoA1, PPARα, and PPARγ in the liver were determined by western blot analysis. Treatment with β3-AR significantly increased the plasma levels of high-density lipoprotein cholesterol and apoA-I, whereas the levels of total cholesterol, triglycerides, and low-density lipoprotein cholesterol decreased. The β3-AR agonist treatment markedly decreased both the FC and the CE concentrations in the aorta compared with the atherosclerotic model mice. The β3-AR agonist increased the mRNA and protein expression levels of apoA-I, PPARα, and PPARg in the liver. This study demonstrates that long-term β3-AR activation can regulate lipid metabolic disorders and reduces the aortic FC and the CE concentrations. These effects may be related to apoA-I, PPARα, and PPARγ. Copyright © 2014 by Lippincott Williams & Wilkins.