Obesity and association with risk of cardiometabolic diseases including type 2 diabetes (T2D) and atherosclerosis.
Obesityis increasingly prevalent and associated with risk of cardiometabolic diseasesincluding type 2 diabetes (T2D) and atherosclerosis. Body mass index, waist circumference, andwaist-to-hip ratio are the measurements currently used for definingobesity. These indirectparametersare often unable to accurately reflect the amount anddistribution of body fat. In contrast, magneticresonance imaging (MRI) and computed tomography (CT) can accurately measureadipose tissue, thus allowing elucidation of the pathological role of obesityin T2D and atherosclerosis. The study ofobesity for its role in cardiometabolic diseases has been hampered due to lackof suitable animal models. Thecommonly used ob/ob and db/db mice develop severeobesity but they do not show increases in atherosclerosis. We have found that Apolipoprotein E knockout(Apoe-/-) mice, an animal model for atherosclerosis, develop obesityand T2D on certain genetic backgrounds after prolonged exposure to a Westerndiet. Among them, male Apoe-/-mice with a C57BL/6 (B6) background develop significant obesity and T2D. Chromosome 9 (Chr9) congenic mice are genetically identical to B6-Apoe-/- mice except for Chr9, which is replaced by genome fromC3H/HeJ mice, and are resistant to T2D andatherosclerosis. Quantitative MRIanalyses showed a 2-fold reduction in subcutaneous abdominal fat,intra-abdominal fat (visceral fat) and total fat but no reduction in non-fattissue volume. Rcn2 is a candidate geneon Chr9 for atherosclerosis we mapped in mice. Rcn2 knockout (Rcn2-/-) mice are resistant to atherosclerosisand show a dramatic reduction in body fat. We will use these two unique mouse models to test the hypothesis thatsubcutaneous and visceral fat in the abdominal region are valuable biomarkersfor predicting the development of T2D and atherosclerosis. The relationshipsof growing subcutaneous and visceral fat with progression of T2D andatherosclerosis will be determined through cross-sectional MRI and biomedicalanalyses of a segregating F2 population and longitudinal analyses of body fat,T2D and atherosclerosis in B6-Apoe-/- and Chr9 congenic mice. We will determine whether reductions insubcutaneous and visceral fat can improve metabolic outcomes andatherosclerosis through genetic and surgical manipulations. Finally, we will develop anautomated image-processing algorithm for measuring subcutaneous and visceralfat in the abdominal region using MRI images. Successful completion of these aimswill substantially advance our understanding of the pathological role ofobesity in cardiometabolic diseases and these advances may lead to newdiagnoses and treatments for cardiometabolic complications in obese patients.
Obesity is a growing epidemic in this countryand globally. The proposed study will determine whether increases insubcutaneous and visceral fat accelerate progression of type 2 diabetes andatherosclerosis and whether reductions of body fat through genetic and surgicalmanipulations improve the conditions in mouse models. New findings will lead to a betterunderstanding of the pathological role of obesity in cardiometabolic diseasesand may provide new strategies for diagnosis and treatment of the diseases.
Graduates or undergraduates will participate in all aspects of the project, including experimental design, collection of data, and writing of manuscripts.