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

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Abstract
Objective— We investigated the effect of a dual peroxisome proliferator-activated receptor (PPAR)α,γ-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 PPARα,γ-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 PPARγ but not PPARα expression in the heart and prevented loss of left ventricular function. Adiponectin correlated positively with PPARγ in the heart and with SF. The agonist had no effect on atherosclerosis in the aortic arch of DKO mice. Conclusions— The dual PPARα,γ-agonist improved insulin sensitivity without affecting cholesterol and triglycerides. This was associated with induction of PPARγ in the heart and prevention of loss of left ventricle function. We investigated the effect of a dual PPARα,γ-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.

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