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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:922.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Peroxisome Proliferator-Activated Receptor-,-Agonist Improves Insulin Sensitivity and Prevents Loss of Left Ventricular Function in Obese Dyslipidemic Mice

Wim Verreth; Javier Ganame; Ann Mertens; Hilde Bernar; Marie-Christine Herregods; Paul Holvoet

From the Atherosclerosis and Metabolism Unit (W.V., A.M., H.B., P.H.) and Division of Cardiology (J.G., M.-C.H.), Department of Molecular and Cardiovascular Research, Katholieke Universiteit Leuven, Belgium.

Correspondence to Paul Holvoet, PhD, Atherosclerosis and Metabolism Unit, Department of Molecular and Cardiovascular Research, Katholieke Universiteit Leuven, Herestraat 49, B-3000 Leuven, Belgium. E-mail paul.holvoet{at}med.kuleuven.ac.be

Objective— We investigated the effect of a dual peroxisome proliferator-activated receptor (PPAR),-agonist on atherosclerosis and cardiac function in mice with combined leptin and low-density lipoprotein receptor deficiency (DKO). In these mice, obesity, diabetes, and hyperlipidemia are associated with accelerated atherosclerosis and loss of cardiac function.

Methods and Results— We treated 12-week-old DKO mice with the PPAR,-agonist (S)-3-(4-(2-carbazol-9-yl-ethoxy) phenyl-2-ethoxy-propionic-acid) for 12 weeks. The agonist lowered free fatty acids with 42% and increased insulin sensitivity with 76%. It had no effect on plasma cholesterol and triglycerides. RT-PCR analysis showed that the agonist increased the expression of fatty acid transport protein-4, fatty acid binding protein-4, glucose transporter-4, hormone-sensitive lipase, and adiponectin in white adipose tissue that was associated with the increase in insulin sensitivity. At 24 weeks, the shortening fraction (SF) of placebo DKO mice was 30% lower than that of C57BL6 mice. The PPAR agonist increased PPAR but not PPAR expression in the heart and prevented loss of left ventricular function. Adiponectin correlated positively with PPAR in the heart and with SF. The agonist had no effect on atherosclerosis in the aortic arch of DKO mice.

Conclusions— The dual PPAR,-agonist improved insulin sensitivity without affecting cholesterol and triglycerides. This was associated with induction of PPAR in the heart and prevention of loss of left ventricle function.

We investigated the effect of a dual PPAR,-agonist on atherosclerosis and cardiac function in mice with combined leptin and LDL receptor deficiency (DKO). In these mice, obesity, diabetes, and hyperlipidemia are associated with accelerated atherosclerosis and loss of cardiac function. The agonist lowered free fatty acids and increased glucose tolerance and insulin sensitivity. It had no effect on plasma cholesterol and triglycerides. It prevented the loss of cardiac function but had no effect on atherosclerosis in DKO mice.

Key Words: cardiovascular disease prevention • echocardiography • insulin resistance • obesity • gene expression

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