Does rosiglitazone affect adiposity and cardiac function in genetic diabetic mice?

Rosiglitazone ((RS)-5-[4-(2-[methyl(pyridin-2-yl)amino]ethoxy)benzyl]thiazolidine-2,4-dione, RGZ)-induced adverse drug effects in diabetic patients were not adequately predicted by current preclinical rodent models. Therefore, we have used the Akita mouse with genetic predisposition to diabetes to unravel the underlying molecular mechanisms. The effect of RGZ on adipose tissue and on cardiac function was evaluated in diabetic Akita mice kept on a high fat-high cholesterol diet (HF-HCD) for 4 months. When compared to wild-type (WT) mice with the same C57BL/6 J genetic background, Akita mice gained significantly less weight (4.4±1.4 g versus 12±0.97 g for WT; P=0.002) and developed less fat (volume of 3.1±1.2 ml versus 16±2.1 ml for WT; P=0.004), associated with adipocyte hypotrophy. Upon treatment with RGZ (10 mg/kg/day), Akita mice showed enhanced weight gain (11±0.70 g; P=0.004 versus untreated Akita mice) and fat volume (7.4±0.63 ml; P<0.05 versus untreated Akita mice), without effects on adipocyte or blood vessel size or on macrophage infiltration in adipose tissues. Akita mice kept on HF-HCD for 4 months with administration of RGZ (30 mg/kg/day) showed increased intraventricular septum thickness and cardiac output, without, however, an effect on fractional shortening or ejection fraction. In conclusion, RGZ promotes adiposity and early signs of hypertrophic cardiomyopathy in the diabetic Akita mouse. Thus, this genetically manipulated model may be suitable to test safety of anti-diabetic drugs.