ABSTRACT
Metabolic diseases such as obesity and atherosclerosis result from complex interactions between environmental factors and genetic variants. A panel of chromosome substitution strains (CSSs) was developed to characterize genetic and dietary factors contributing to metabolic diseases and other biological traits and biomedical conditions. Our goal here was to identify quantitative trait loci (QTLs) contributing to obesity, energy expenditure, and atherosclerosis. Parental strains C57BL/6 and A/J together with a panel of 21 CSSs derived from these progenitors were subjected to chronic feeding of rodent chow and atherosclerotic (females) or diabetogenic (males) test diets, and evaluated for a variety of metabolic phenotypes including several traits unique to this report, namely fat pad weights, energy balance, and atherosclerosis. A total of 297 QTLs across 35 traits were discovered, two of which provided significant protection from atherosclerosis, and several dozen QTLs modulated body weight, body composition, and circulating lipid levels in females and males. While several QTLs confirmed previous reports, most QTLs were novel. Finally, we applied the CSS quantitative genetic approach to energy balance, and identified three novel QTLs controlling energy expenditure and one QTL modulating food intake. Overall, we identified many new QTLs and phenotyped several novel traits in this mouse model of diet-induced metabolic diseases.
Subject(s)
Atherosclerosis/genetics , Energy Metabolism/genetics , Obesity/genetics , Animals , Body Composition , Body Weight , Chromosomes, Mammalian/genetics , Diet, High-Fat/adverse effects , Female , Genetic Association Studies , Genetic Predisposition to Disease , Male , Mice, Inbred C57BL , Phenotype , Quantitative Trait LociABSTRACT
The aims of this study were to determine whether mice induced to become obese also exhibited accelerated atherosclerosis, and to determine whether obesity itself or dyslipidemia associated with obesity enhanced atherosclerosis. Wild-type (C57BL/6) mice and mice deficient for the low density lipoprotein receptor (LDLR-/-) or apolipoprotein E (apoE-/-) were fed a low fat, rodent chow diet or a high fat, high sucrose (diabetogenic) diet to induce obesity. As compared with wild-type mice, diabetogenic diet-fed LDLR-/- mice became more obese and developed severe dyslipidemia. Consequently, atherosclerotic lesions were increased in the LDLR-/- mice 3.7-fold over chow fed values. ApoE-/- mice showed weight gain profiles similar to those observed for wild-type mice. However, no differences in plasma lipid levels, lipoprotein profiles or atherosclerotic lesion areas were observed between chow-fed and diabetogenic diet-fed apoE-/- mice. These data demonstrate that lipid storage and partitioning as mediated by the low density lipoproteins (LDL) receptor or apoE-/- have profound and opposing consequences for dyslipidemia and atherosclerosis susceptibility associated with obesity.
Subject(s)
Apolipoproteins E/deficiency , Coronary Artery Disease/immunology , Coronary Artery Disease/metabolism , Immunity, Innate , Obesity/immunology , Obesity/metabolism , Receptors, LDL/deficiency , Animals , Apolipoproteins B/drug effects , Apolipoproteins B/metabolism , Apolipoproteins E/blood , Apolipoproteins E/drug effects , Biomarkers/blood , Body Weight/drug effects , Chromatography, High Pressure Liquid , Dietary Fats/administration & dosage , Dietary Fats/adverse effects , Disease Models, Animal , Disease Susceptibility , Hyperlipidemias/etiology , Hyperlipidemias/metabolism , Lipoproteins, HDL/drug effects , Lipoproteins, HDL/metabolism , Lipoproteins, LDL/drug effects , Lipoproteins, LDL/metabolism , Lipoproteins, VLDL/drug effects , Lipoproteins, VLDL/metabolism , Magnetic Resonance Spectroscopy , Male , Mice , Mice, Inbred C57BL , Models, Cardiovascular , Predictive Value of Tests , Receptors, LDL/blood , Receptors, LDL/drug effects , Statistics as Topic , Triglycerides/metabolismABSTRACT
Inflammatory processes are involved with all phases of atherosclerotic lesion growth. Tumor necrosis factor-alpha (TNFalpha) is an inflammatory cytokine that is thought to contribute to lesion development. Lymphotoxin-alpha (LTalpha) is also a proinflammatory cytokine with homology to TNFalpha. However, its presence or function in lesion development has not been investigated. To study the role of these molecules in atherosclerosis, the expression of these cytokines in atherosclerotic lesions was examined. The presence of both cytokines was observed within aortic sinus fatty streak lesions. To determine the function of these molecules in regulating lesion growth, mice deficient for TNFalpha or LTalpha were examined for induction of atherosclerosis. Surprisingly, loss of TNFalpha did not alter lesion development compared with wild-type mice. This brings doubt to the generally held concept that TNFalpha is a "proatherogenic cytokine." However, LTalpha deficiency resulted in a 62% reduction in lesion size. This demonstrates an unexpected role for LTalpha in promoting lesion growth. The presence of LTalpha was observed in aortic sinus lesions suggesting a direct role of LTalpha in modulating lesion growth. To determine which receptor mediated these responses, diet-induced atherosclerosis in mice deficient for each of the TNF receptors, termed p55 and p75, was examined. Results demonstrated that loss of p55 resulted in increased lesion development, but loss of p75 did not alter lesion size. The disparity in results between ligand- and receptor-deficient mice suggests there are undefined members of the TNF ligand and receptor signaling pathway involved with regulating atherogenesis.
