Abstract
The heart of leptin-deficient ob/ob mice is characterized by pathologic left ventricular hypertrophy along with elevated triglyceride (TG) content, increased stearoyl-CoA desaturase (SCD) activity, and increased myocyte apoptosis. In the present study, using an ob/ob;SCD1(-/-) mouse model, we tested the hypothesis that lack of SCD1 could improve steatosis and left ventricle (LV) function in leptin deficiency. We show that disruption of the SCD1 gene improves cardiac function in ob/ob mice by correcting systolic and diastolic dysfunction without affecting levels of plasma TG and FFA. The improvement is associated with reduced expression of genes involved in FA transport and lipid synthesis in the heart, as well as reduction in cardiac FFA, diacylglycerol, TG, and ceramide levels. The rate of FA beta-oxidation is also significantly lower in the heart of ob/ob;SCD1(-/-) mice compared with ob/ob controls. Moreover, SCD1 deficiency reduces cardiac apoptosis in ob/ob mice due to increased expression of antiapoptotic factor Bcl-2 and inhibition of inducible nitric oxide synthase and caspase-3 activities. Reduction in myocardial lipid accumulation and inhibition of apoptosis appear to be one of the main mechanisms responsible for improved LV function in ob/ob mice caused by SCD1 deficiency.
Highlights
The heart of leptin-deficient ob/ob mice is characterized by pathologic left ventricular hypertrophy along with elevated triglyceride (TG) content, increased stearoylCoA desaturase (SCD) activity, and increased myocyte apoptosis
We show that SCD1 deficiency corrects these known pathologies of leptin deficiency and significantly improves left ventricle (LV) function in ob/ob mice even though it does not affect hypertriglyceridemia or glucose intolerance in ob/ob mice [18]
The improvement in cardiac function in ob/ob;SCD1Ϫ/Ϫ mice was accompanied by decreased intracellular neutral lipid and ceramide contents in the heart and inhibition of the apoptotic pathway(s) regulated by lipids in the LV cardiomyocytes
Summary
The heart of leptin-deficient ob/ob mice is characterized by pathologic left ventricular hypertrophy along with elevated triglyceride (TG) content, increased stearoylCoA desaturase (SCD) activity, and increased myocyte apoptosis. The improvement is associated with reduced expression of genes involved in FA transport and lipid synthesis in the heart, as well as reduction in cardiac FFA, diacylglycerol, TG, and ceramide levels. SCD1 deficiency reduces cardiac apoptosis in ob/ob mice due to increased expression of antiapoptotic factor Bcl-2 and inhibition of inducible nitric oxide synthase and caspase-3 activities. Reduction in myocardial lipid accumulation and inhibition of apoptosis appear to be one of the main mechanisms responsible for improved LV function in ob/ob mice caused by SCD1 deficiency.—Dobrzyn, P., A. The important role for ceramide-induced apoptosis in obesity-related cardiomyopathies has been shown in many animal models, including leptin-insensitive ZDF rats [4], leptin-deficient ob/ob mice [5, 6], and a mouse model of heart disease induced by cardiomyocyte-specific overexpression of acyl-CoA synthase [7].
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