In Vivo Knockdown of p85α with an Antisense Oligonucleotide Improves Insulin Sensitivity in Lep ^ob/ob and Diet-induced Obese Mice

Abstract

Phosphoinositide 3-kinase is a key signaling intermediate necessary for the metabolic actions of insulin. In this study, we assessed the effects of in vivo knockdown of the p85α subunit of phosphoinositide 3-kinase on insulin sensitivity, using an antisense oligonucleotide, in lean mice, diet-induced obese mice, and obese leptin-deficient Lep ^ob/ob mice. Mice were injected with either p85α-targeted antisense oligonucleotide or saline twice weekly for 4 weeks. Fasting levels of glycemia and insulinemia and insulin and glucose tolerance tests were used to determine insulin sensitivity. Western blot analysis and real-time polyacrylamide chain reaction were used to assess p85α protein and mRNA expression. In vivo administration of antisense oligonucleotide resulted in 50 and 60% knockdown of liver p85α protein and mRNA, respectively, in the lean, diet-induced obese and Lep ^ob/ob mice. This was associated with increased phosphoinositide 3-kinase activity and improved insulin sensitivity in diet-induced obese and Lep ^ob/ob mice. Thus, p85α could be an important therapeutic target to ameliorate insulin resistance.

Key words

PI3-kinase - insulin resistance - obesity

References

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