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Targeting Foxo1 in Mice Using Antisense Oligonucleotide Improves Hepatic and Peripheral Insulin Action

¹ Howard Hughes Medical Institute, Chevy Chase, Maryland
² Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
³ Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut
⁴ Isis Pharmaceuticals, Carlsbad, California
⁵ Amgen, Thousand Oaks, California

Address correspondence and reprint requests to Gerald I. Shulman, MD, PhD, TAC S269, P.O. Box 9012, 300 Cedar St., Yale University School of Medicine, New Haven, CT 06510. E-mail: gerald.shulman{at}yale.edu

Abbreviations: 2-DG, 2-deoxyglucose; ASO, antisense oligonucleotide; DAG, diacylglycerol; DIO, diet-induced obesity; EGP, endogenous glucose production; FBS, fetal bovine serum; G6Pase, glucose-6-phosphatase; PPAR, peroxisome proliferator–activated receptor; TG, triglyceride; WAT, white adipose tissue

Fasting hyperglycemia, a prominent finding in diabetes, is primarily due to increased gluconeogenesis. The transcription factor Foxo1 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 Foxo1 expression. Here we show the effect of such therapy on insulin resistance in mice with diet-induced obesity (DIO). Reducing Foxo1 mRNA expression with ASO therapy in mouse hepatocytes decreased levels of Foxo1 protein and mRNA expression of PEPCK by 48 ± 4% and G6Pase by 64 ± 3%. In mice with DIO and insulin resistance, Foxo1 ASO therapy lowered plasma glucose concentration and the rate of basal endogenous glucose production. In addition, Foxo1 ASO therapy lowered both hepatic triglyceride and diacylglycerol content and improved hepatic insulin sensitivity. Foxo1 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, Foxo1 ASO therapy improved both hepatic insulin and peripheral insulin action. Foxo1 is a potential therapeutic target for improving insulin resistance.

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