Abstract 9148: Inhibition of Endothelial Senescence Ameliorates Insulin Resistance of Obese Mice
Various stimuli can induce irreversible cell growth arrest, termed cellular senescence. This response is controlled by negative regulators of the cell cycle such as p53. Accumulating evidence suggests a potential relationship between cellular senescence and age-associated diseases including type 2 diabetes. Here we show a crucial role for endothelial p53 in the regulation of insulin resistance. We found that treatment of endothelial cells with high glucose and palmitate synergistically increased p53 expression. Consistent with the in vitro results, endothelial expression of p53 was markedly up-regulated when the mice were fed a high-calorie diet, suggesting that excessive calorie intake promotes endothelial senescence. To investigate the role of endothelial p53 in type 2 diabetes, we analyzed metabolic parameters in endothelial cell-specific p53 conditional knockout (ECp53CKO) mice on a high-calorie diet. In spite of no difference in dietary intake, ECp53CKO mice had a significantly smaller weight and less fat accumulation than control mice. Moreover, ECp53CKO mice showed better insulin sensitivity and glucose tolerance than control littermates. ECp53CKO mice demonstrated a significant increase in oxygen consumption and had a higher core body temperature compared with control mice. Next we considered some assumed mechanisms of relationship between endothelial cell p53 expression and metabolic disorders. As a result, we found that ECp53CKO mice had higher glucose uptake in skeletal muscles than control. These results indicate that inhibition of endothelial senescence ameliorates insulin resistance by increasing energy consumption via glucose uptake and suggest that endothelial p53 will be a novel therapeutic target for type 2 diabetes.
- © 2011 by American Heart Association, Inc.