Abstract
The "lipotoxic footprint" of cardiac maladaptation in diet-induced obesity is poorly defined. We investigated how manipulation of dietary lipid and carbohydrate influenced potential lipotoxic species in the failing heart. In Wistar rats, contractile dysfunction develops at 48 weeks on a high-fat/high-carbohydrate "Western" diet, but not on low-fat/high-carbohydrate or high-fat diets. Cardiac content of the lipotoxic candidates--diacylglycerol, ceramide, lipid peroxide, and long-chain acyl-CoA species--was measured at different time points by high-performance liquid chromatography and biochemical assays, as was lipogenic capacity in the heart and liver by qRT-PCR and radiometric assays. Changes in membranes fluidity were also monitored using fluorescence polarization. We report that Western feeding induced a 40% decrease in myocardial palmitoleoyl-CoA content and a similar decrease in the unsaturated-to-saturated fatty acid ratio. These changes were associated with impaired cardiac mitochondrial membrane fluidity. At the same time, hepatic lipogenic capacity was increased in animals fed Western diet (+270% fatty acid elongase activity compared with high-fat diet), while fatty acid desaturase activity decreased over time. Our findings suggest that dysregulation of lipogenesis is a significant component of heart failure in diet-induced obesity.
Highlights
The “lipotoxic footprint” of cardiac maladaptation in diet-induced obesity is poorly defined
Triacylglycerol levels followed insulin levels: Plasma triacylglycerol was higher with the low-fat/high-carbohydrate diet, and the Western diet induced an intermediate raise that became significantly higher than high-fat diet in the long term (Table 3)
Among all the commonly described lipotoxic molecules, we identified long-chain acyl-CoA (LCACoA) species as the main potential contributor for contractile dysfunction in our rat models of diet-induced obesity
Summary
The “lipotoxic footprint” of cardiac maladaptation in diet-induced obesity is poorly defined. We report that Western feeding induced a 40% decrease in myocardial palmitoleoyl-CoA content and a similar decrease in the unsaturated-to-saturated fatty acid ratio These changes were associated with impaired cardiac mitochondrial membrane fluidity. Increased lipid influx in the heart [9, 10], decreased mobilization of triacylglycerol reserves [11], or increased fatty acid metabolism [12,13,14] all are associated with metabolic alterations that mimic those of diabetes, including hypertrophy of the heart and contractile dysfunction These animal studies have led to the identification of the lipid molecules that are potential culprits for impaired cardiac function. These lipid species may impair insulin signaling through increased serine phosphorylation of the insulin receptor and insulin receptor substrate 1 and/or reduced serine phosphorylation of PKB/Akt [19, 20]
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