Relationship of p53 accumulation in peripheral tissues of high-fat diet-induced obese rats with decrease in metabolic and oncogenic signaling of insulin

• Overexpression of p53 in peripheral tissues of diet-induced rats in addition to adipose tissue.
• PTEN elevation in peripheral tissues in addition to adipose tissues.
• AKT inactivation in peripheral tissues of obese rats.
• Improvement of insulin action by systemic inhibition of p53 in obese rats.

This paper aimed to explore the role of p53 in adipose and some other peripheral tissues of a diet-induced obese model and targeted it using pharmacological approach to ameliorate diet-induced insulin resistance.Five week old male Wistar rats were randomly divided into three groups and fed on low-fat diet (13% control lean group), high-fat diet (41% obese group), or high-fat diet plus a single dose of pifithrin-α in the end of experiments (PFT group). Insulin, glucose, and other serum parameters were analyzed by standard colorimetric kits. Protein levels were evaluated by immunoblotting and immunofluorescence methods.After 12 weeks, both body weight and insulin resistance were significantly higher in obese rats than in the control ones. P53 and PTEN protein levels were markedly elevated in peripheral tissues in addition to adipose tissues. AKT activation was decreased in the peripheral tissues of obese rats and was in correlation with the increase of p53 and PTEN level. Systemic pifithrin-α administration considerably diminished p53 levels and ameliorated AKT phosphorylation in all peripheral tissues including adipose tissues. Interestingly, the systemic inhibition of p53 was in correlation with improving insulin glucose at serum level. The present results clearly showed that p53 activation in peripheral tissues was in correlation with decreased insulin action. These results indicated p53 activation in the peripheral tissues of obese subjects as a protective mechanism against chronic insulin elevation, suggested that p53 could be a new target for the treatment of type 2 diabetes.