In Vivo Knockdown Of P85 Alpha With An Antisense Oligonucleotide Improves Insulin Sensitivity In Lep(Ob/Ob) And Diet-Induced Obese Mice
HORMONE AND METABOLIC RESEARCH(2009)
摘要
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 p85 alpha 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 p85 alpha-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 p85 alpha protein and mRNA expression. In vivo administration of antisense oligonucleotide resulted in 50 and 60% knockdown of liver p85 alpha 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, p85 alpha could be an important therapeutic target to ameliorate insulin resistance.
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关键词
PI3-kinase, insulin resistance, obesity
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