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 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.
Samuel
Varman T
VT
TAC S269, P.O. Box 9012, 300 Cedar St., Yale University School of Medicine, New Haven, CT 06510, USA.
Choi
Cheol Soo
CS
Phillips
Trevor G
TG
Romanelli
Anthony J
AJ
Geisler
John G
JG
Bhanot
Sanjay
S
McKay
Robert
R
Monia
Brett
B
Shutter
John R
JR
Lindberg
Richard A
RA
Shulman
Gerald I
GI
Veniant
Murielle M
MM
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D007328:Insulin / Q000502:physiology*; D007700:Kinetics; D008099:Liver / Q000502:physiology*; D051379:Mice; D016376:Oligonucleotides, Antisense; D000637:Transaminases / Q000378:metabolism
D001786:Blood Glucose; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D016376:Oligonucleotides, Antisense; D000637:Transaminases