In vivo knockdown of p85alpha with an antisense oligonucleotide improves insulin sensitivity in Lep(ob/ob) and diet-induced obese mice.
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 p85alpha 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 p85alpha-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 p85alpha protein and mRNA expression. IN VIVO administration of antisense oligonucleotide resulted in 50 and 60% knockdown of liver p85alpha 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, p85alpha could be an important therapeutic target to ameliorate insulin resistance.
Moriarty
M W
MW
Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA. Megan.Moriarty@ucdenver.edu
McCurdy
C E
CE
Janssen
R C
RC
Shaw
T
T
Leitner
J W
JW
Friedman
J E
JE
Draznin
B
B
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D015153:Blotting, Western; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D012313:RNA; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001786:Blood Glucose; D007328:Insulin; D016376:Oligonucleotides, Antisense; D012313:RNA; D019869:Phosphatidylinositol 3-Kinases