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

Abstract

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. Key Words: cardiovascular disease prevention Ⅲ echocardiography Ⅲ insulin resistance Ⅲ obesity Ⅲ gene expression C ardiovascular diseases remain the leading cause of mortality in the Western societies. Several risk factors predispose to cardiovascular diseases, including the metabolic syndrome components diabetes, obesity, insulin resistance, dyslipidemia, and hypertension. It has been demonstrated that nuclear peroxisome proliferator-activated receptor (PPAR) deactivation (mainly obesity-related) is a key phase of metabolic syndrome initiation. [1][2][3] The identification of the nuclear receptors PPAR␥ and PPAR␣ as being the primary targets for the insulin-sensitizing thiazolidinediones and the lipid-lowering fibrates, respectively, has provided opportunities for the identification of novel compounds for the treatment of the metabolic syndrome. Conclusions-TheRecently, we demonstrated that several metabolic syndrome components (obesity, dyslipidemia, diabetes, and hypertension) in mice with combined leptin and low-density lipoprotein receptor deficiency (DKO) are associated with increased oxidative stress, accelerated atherosclerosis, and impaired cardiovascular function. 4,5 Compared with lean mice, PPAR␣ and PPAR␥ expression were downregulated in DKO mice. Diet restriction-induced weight loss resulted in increased expression of PPAR␣ and PPAR␥ in the adipose tissue (AT), the aortic arch, and the heart. These changes in expression were associated with increased insulin sensitivity, decreased hypertriglyceridemia, reduced mean 24-hour blood pressure and heart rate, restored circadian variations of blood pressure and heart rate, increased ejection fraction, and reduced atherosclerosis. To further study the role of PP...

Low-grade inflammation in overweight and obese adults is affected by weight loss program

“…Decreased serum total cholesterol levels may further decrease the risk of CVD and chronic inflammation. A possible explanation for production of adiponectin on weight loss is probably activation of the peroxisome proliferator-activated receptor gamma (PPAR-c), a pathway which is activated by a negative energy balance and weight loss [36]. Therefore, we suggest that weight loss is more important in activation of PPAR-c than a negative energy balance.…”

Mouse models of the metabolic syndrome

“…Furthermore, these mice spontaneously develop atherosclerotic lesions, and are thus very useful for studying the role of obesity in cardiovascular disease. Our group and others have used this model to study therapeutic treatments for MetS, as well as to study mechanisms of obesity-related hyperlipidemia (Mertens et al, 2003;Verreth et al, 2004;Hasty et al, 2006;Verreth et al, 2006;Coenen et al, 2007a ;LDLR -/-mice with the exception that they have very high circulating leptin levels (Gruen et al, 2006). We have also crossed the Lep ob/ob and LepR db/db mice onto an apoE -/-background, and these mice are also obese, insulin resistant and hyperlipidemic (Gruen et al, 2006;Atkinson et al, 2008 (Fig.…”

PPAR Ligands: Are They Potential Agents for Cardiovascular Disorders?

“…By activating both PPAR ␣ and PPAR ␥ receptors, they simultaneously reduce atherogenic triglycerides, raise cardioprotective HDL levels, and improve insulin sensitivity. PPAR ␣ / ␥ dual agonists such as (S)-3-[4-(2-carbazol-9-yl-ethoxy) phenyl-2-ethoxy-propionic acid] improve the insulin sensitivity and prevent loss of left ventricular function in obese mice [81] . A study evaluating the possible role of dual PPAR ␣ / ␥ in pressure-overload-induced pathological cardiac hypertrophy is currently under way in our laboratory.…”