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Published on: September 26, 2018
Paradoxical reduction of atherosclerosis in apoE-deficient mice with obesity-related type 2 diabetes
L G Lyngdorf1, S Gregersen, A Daugherty
1Department of Cardiology and Institute of Experimental Clinical Research, Aarhus University Hospital (Skejby Sygehus), DK-8200 Aarhus N, Denmark. linegrly@yahoo.com
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.
Insights
Obese, insulin-resistant mice showed less atherosclerosis than lean controls. Food restriction also reduced atherosclerosis in these atherosclerosis models, questioning mouse model relevance for obesity-related diabetes studies.
Area of Science:
- Cardiovascular Research
- Metabolic Syndrome Research
- Animal Models of Disease
Background:
- Atherosclerosis is a complex disease influenced by metabolic factors like obesity and insulin resistance.
- Apolipoprotein E-deficient (ApoE(-/-)) mice are a common model for studying atherosclerosis.
- The relationship between obesity-induced type 2 diabetes and atherosclerosis development requires further elucidation.
Purpose of the Study:
- To investigate the impact of obesity and insulin resistance on atherosclerosis development in ApoE(-/-) mice.
- To assess the effect of food restriction on atherosclerosis in ApoE(-/-) mice.
- To evaluate the utility of ApoE(-/-) mice in modeling obesity-related diabetes and atherosclerosis.
Main Methods:
- Sixty-eight ApoE(-/-) mice were divided into three groups: control, gold thioglucose (GTG)-injected (obesity model), and food-restricted.
- Obesity was induced via GTG injection targeting the hypothalamic satiety center.
- Food-restricted mice received 25% less chow than ad libitum-fed controls for 4 months.
Main Results:
- GTG-injected mice became significantly overweight, obese, hypertriglyceridemic, insulin-resistant, hyperinsulinemic, and hyperglycemic compared to controls.
- Unexpectedly, obese and diabetic mice exhibited significantly less atherosclerosis than lean, non-diabetic control mice.
- Food-restricted mice also showed reduced atherosclerosis development compared to control mice.
Conclusions:
- Obesity and diabetes in this ApoE(-/-) mouse model were paradoxically associated with reduced atherosclerosis.
- These findings raise questions about the validity of using ApoE(-/-) mice to study the link between obesity-related type 2 diabetes and atherosclerosis.
- The relevance of results from ApoE(-/-) mice with attenuated weight gain in intervention studies may be limited.
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