A Diet-Induced Model of Insulin Resistance and Cardiomyopathy
Diabetes is associated with a 2- to 3-fold ? in risk for congestive heart failure (CHF), due primarily to diastolic dysfunction scarring. We recently that leptin-deficient, female BTBR mice (BTBRob/ob) develop cardiomyopathy, with a 24-25% ? in heart weight, a 5-fold ? in fibrosis, and a 6-fold ? in inflammation. However, BTBRob/ob mice are derived from heterozygous matings, and the cardiomyopathy phenotype is most pronounced in females, Thus, only 1/8 of littermates develop significant cardiomyopathy. Therefore, we propose to the study whether the cardiomyopathy phenotype can be replicated in the background, BTBR strain through use of a “diabetogenic” diet (“DD) high in fat (58% of calories) and refined sugar (14% of calories). We also will determine whether adding 0.15% cholesterol to the diet (“DDC”) might worsen the cardiomyopathy. In preliminary studies, both female and male BTBR mice become highly resistant to insulin after as little as 8 weeks on DD or DDC. By 16 weeks, as compared to Chow, mice on DD or DDC have about 24-38% higher body weights, similar blood pressures and fasting glucose levels, but 17-18% higher heart weights (P<0.01 for both diets for both genders). Moreover, BTBR mice continue to gain weight on DD and DDC, so their cardiomyopathy might progress with longer-term feeding. Therefore, we propose to study the short-term (16 week) and long-term (26 week) effects of feeding DD and DDC on cardiac hypertrophy, fibrosis and inflammation in BTBR mice. Demonstration that diets high in fat and refined sugars may induce cardiomyopathy in BTBR mice would validate a powerful, efficient, and relatively inexpensive tool to investigate the molecular mechanisms by which insulin resistance causes cardiomyopathy and CHF.

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