Abstract
Dysfunction of the melanocortin system can result in severe obesity accompanied with dyslipidemia and symptoms of the metabolic syndrome but the effect on vascular atherogenesis is not known. To study the impact of obesity and dyslipidemia on the cardiovascular system, we generated mice double-deficient for the melanocortin type 4 receptor (Mc4rmut mice) and the LDL receptor (Ldlr-/- mice). Mc4rmut mice develop obesity due to hyperphagia. Double-mutant mice (Mc4rmut;Ldlr-/-) exhibited massive increases in body weight, plasma cholesterol and triacylglycerol levels and developed atherosclerosis. Atherosclerotic lesion size was affected throughout the aortic root and brachiocephalic artery not only under semisynthetic, cholesterol-containing diet but also under cholesterol-free standard chow. The Mc4rmut mice developed a hepatic steatosis which contributes to increased plasma cholesterol levels even under cholesterol-free standard chow. Transcripts of cholesterol biosynthesis components and liver cholesterol levels did not significantly differ between wild-type and all mutant mouse strains but RNA sequencing data and biochemical measurements point to an altered bile acid elimination in Mc4rmut;Ldlr-/-. Therefore, the unchanged endogenous cholesterol biosynthesis together with a reduced hepatic VLDL and LDL-cholesterol clearance most likely led to increased plasma lipid levels and consequently to atherosclerosis in this animal model. Our data indicate that dysfunction of the melanocortin-regulated food intake and the resulting obesity significantly add to the proatherogenic lipoprotein profile caused by LDL receptor deficiency and, therefore, can be regarded as relevant risk factor for atherosclerosis.
Highlights
Obesity is a global epidemic with significant morbidity and mortality affecting both adults and children
melanocortin type 4 receptor (Mc4r) deficiency led to a significant increase in body weight in male (45%) and female (50%) mice fed on standard chow and in male (30%) and female (62%) mice on a semisynthetic diet (Table 1)
The difference of weight due to Mc4r deficiency was found on the low-density lipoprotein receptor (Ldlr)-/- background
Summary
Obesity is a global epidemic with significant morbidity and mortality affecting both adults and children. Dyslipidemia and hypertension are often found in obese patients. This symptom complex is referred to as the metabolic syndrome [1] which increases the risk of diabetes and cardiovascular diseases [2]. Mouse models are widely used to study obesity, the metabolic syndrome, dysfunctions of the lipid metabolism, and atherosclerosis. Mouse strains deficient for apolipoprotein E (apoE) [4] and the low-density lipoprotein receptor (Ldlr) [5] have been broadly used as models for atherosclerosis. Mice deficient for the Ldlr (Ldlr-/- mice) have high levels of low-density lipoprotein (LDL) and can develop massive atherosclerotic lesions depending on the diet [6]. Ldlr-/- mice are models for hyperlipidemia and atherosclerosis but the effect of a metabolic syndrome cannot be addressed along with lipid disorders in this model
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