Targeting Foxo1 in mice using antisense oligonucleotide improves hepatic and peripheral insulin action

Fasting hyperglycemia, a prominent finding in diabetes, is primarily due to increased gluconeogenesis. The transcription factor Foxol links insulin signaling to decreased transcription of PEPCK and glucose-6-phosphatase (G6Pase) and provides a possible therapeutic target in insulin-resistant states. Synthetic, optimized antisense oligonucleotides (ASOs) specifically inhibit Foxol expression. Here we show the effect of such therapy on insulin resistance in mice with diet-induced obesity (DIO). Reducing Foxol mRNA expression with ASO therapy in mouse hepatocytes decreased levels of Foxol protein and mRNA expression of PEPCK by 48 +/- 4% and G6Pase by 64 +/- 3%. In mice with DIO and insulin resistance, Foxol ASO therapy lowered plasma glucose concentration and the rate of basal endogenous glucose production. In addition, Foxol ASO therapy lowered both hepatic triglyceride and diacylglycerol content and improved hepatic insulin sensitivity. Foxol ASO also improved adipocyte insulin action. At a tissue-specific level, this manifested as improved insulin-mediated 2-deoxyglucose uptake and suppression of lipolysis. On a whole-body level, the result was improved glucose tolerance after an intraperitoneal glucose load and increased insulin-stimulated whole-body glucose disposal during a hyperinsulinemic-euglycemic clamp. In conclusion, Foxol ASO therapy improved both hepatic insulin and peripheral insulin action. Foxol is a potential therapeutic target for improving insulin resistance.