Lipotoxic heart disease in obese rats: implications for human obesity

Abstract

To determine the mechanism of the cardiac dilatation and reduced contractility of obese Zucker Diabetic Fatty rats, myocardial triacylglycerol (TG) was assayed chemically and morphologically. TG was high because of underexpression of fatty acid oxidative enzymes and their transcription factor, peroxisome proliferator-activated receptor-alpha. Levels of ceramide, a mediator of apoptosis, were 2-3 times those of controls and inducible nitric oxide synthase levels were 4 times greater than normal. Myocardial DNA laddering, an index of apoptosis, reached 20 times the normal level. Troglitazone therapy lowered myocardial TG and ceramide and completely prevented DNA laddering and loss of cardiac function. In this paper, we conclude that cardiac dysfunction in obesity is caused by lipoapoptosis and is prevented by reducing cardiac lipids.

Figures

Figure 1

Echocardiographic images from a normal lean ZDF (+/+) rat at age 20 weeks and an age-matched obese ZDF (fa/fa) rat. The dotted lines represent the cavity area for end-diastole (Left) and end-systole (Right). Both the end-diastolic and end-systolic areas are much larger in the fa/fa rat, indicating a dilated ventricle with subnormal systolic contraction.

Figure 2

(a) TG content in the myocardium of lean (+/+) and obese (fa/fa) ZDF rats at 7 and 14 weeks of age (P < 0.05). (b) Volume densities of lipid droplets in cardiac myocytes of lean (+/+) controls and obese (fa/fa) ZDF rats (P < 0.001).

Figure 3

Myocardial mRNA of L-CPT-1 (B) and ACO (C), enzymes of FA oxidation, and their transcription factor, PPARα (D), and an enzyme of FA esterification, GPAT (A). mRNA values were semiquantified by reverse transcriptase–PCR and normalized for β-actin mRNA.

Figure 4

(a) Percentage of myocardial DNA laddering, an index of apoptosis, obtained at 7 and 14 weeks of age in lean (+/+) and obese (fa/fa) ZDF rats (*, P < 0.01). (b) Myocardial ceramide levels in lean (+/+) and obese (fa/fa) ZDF rats at 7 and 14 weeks of age (*, P < 0.01). (c) Myocardial iNOS mRNA in lean (+/+) and obese (fa/fa) ZDF rats at 7 and 14 weeks of age.

Figure 5

(a) The effect of TGZ treatment on myocardial TG in obese (fa/fa) ZDF rats and untreated littermates (P < 0.01). (b) Morphometric quantification of lipid droplets in the myocardium of TGZ-treated obese ZDF rats and of untreated controls (P < 0.001). (c) Myocardial ceramide content in TGZ-treated and in untreated obese ZDF rats (P < 0.01). (d) Myocardial DNA laddering in TGZ-treated and untreated obese ZDF rats (P < 0.01). (e). Fractional area shortening, an index of myocardial contractile function, in TGZ-treated and untreated obese ZDF rats (*, P < 0.01; n = 4). □ = lean (+/+) rats; ■ = untreated ZDF (fa/fa) rats; ▨ = TGZ-treated ZDF (fa/fa) rats.

Figure 6

Pair of thin sections of the myocardium of an 18-week-old untreated obese (fa/fa) ZDF rat (Left) and a TGZ-treated obese (fa/fa + TGZ) ZDF rat (Right). Note the reduction of lipid droplets (|) in TGZ-treated animals. The quantitative evaluation of the lipid accumulation is shown in Fig. 5b.