Paradoxical reduction of atherosclerosis in apoE-deficient mice with obesity-related type 2 diabetes

Objective: The effect of obesity and insulin resistance on the development of atherosclerosis was evaluated in apoE-deficient (ApoE^-/-) mice. A previously described obesity model, in which the hypothalamic satiety center can be destroyed by a single gold thioglucose (GTG) injection, was used. To evaluate the effect of starvation on atherosclerosis ApoE^-/- mice were food-restricted with 25% less chow than ad libitum-fed control mice. Methods: Sixty-eight ApoE^-/- mice were allocated into a control group (n=20), a GTG-injected group (n=28), and a food-restricted group (n=20). The control and food-restricted mice were injected with saline instead of GTG. The control and GTG-injected mice had free access to food, and all mice had free access to water during the study period. Results: After 4 months, the GTG-injected mice were significantly overweight (mean body weight (g): 33±2.11 vs. 23±0.24 and 17±0.31 in control and food-restricted mice, respectively), obese, hypertriglyceridemic, insulin-resistant, hyperinsulinemic (mean plasma insulin (ng/ml): 2.45 and 0.43 in obese and control mice, respectively), and hyperglycemic (mean plasma glucose (mmol/l): 11.03 and 7.80 in obese and control mice, respectively). Unexpectedly, these obese and diabetic mice developed significantly less atherosclerosis compared with lean non-diabetic control mice. Food-restricted mice also developed less atherosclerosis compared to control mice. Conclusions: These findings may question the usefulness of mouse models in studying the relation of obesity-related type 2 diabetes to atherosclerosis and also the relevance of results obtained in apoE^-/- mice with reduced weight gain during intervention.