Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism
Michihiro Matsumoto, … , Tadahiro Kitamura, Domenico Accili
Michihiro Matsumoto, … , Tadahiro Kitamura, Domenico Accili
Published September 1, 2006
Citation Information: J Clin Invest. 2006;116(9):2464-2472. https://doi.org/10.1172/JCI27047.
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Research Article Metabolism

Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism

Abstract

Hepatic insulin resistance affects both carbohydrate and lipid metabolism. It has been proposed that insulin controls these 2 metabolic branches through distinct signaling pathways. FoxO transcription factors are considered effectors of the pathway regulating hepatic glucose production. Here we show that adenoviral delivery of constitutively nuclear forkhead box O1 (FoxO1) to mouse liver results in steatosis arising from increased triglyceride accumulation and decreased fatty acid oxidation. FoxO1 gain of function paradoxically increased insulin sensitivity by promoting Akt phosphorylation, while FoxO1 inhibition via siRNA decreased it. We show that FoxO1 regulation of Akt phosphorylation does not require DNA binding and is associated with repression of the pseudokinase tribble 3 (Trb3), a modulator of Akt activity. This unexpected dual role of FoxO1 in promoting insulin sensitivity and lipid synthesis in addition to glucose production has the potential to explain the peculiar admixture of insulin resistance and sensitivity that is commonly observed in the metabolic syndrome.

Authors

Michihiro Matsumoto, Seongah Han, Tadahiro Kitamura, Domenico Accili

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Figure 1

FoxO1 overexpression in liver.

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FoxO1 overexpression in liver. Macroscopic view of livers (A) and oil re...
Macroscopic view of livers (A) and oil red O staining of liver sections (B) from representative mice injected with control empty adenovirus or adenovirus expressing FoxO1ADA and collected after an overnight fast. (C) Liver TG content in fasted and ad libitum–fed FoxO1ADA or control mice (n = 6 for each group). (D) Gene expression analysis by real-time RT-PCR in livers from ad libitum-fed control (n = 6; white bars) or FoxO1ADA mice (n = 6; black bars). Each PCR was carried out in triplicate. *P < 0.05 and **P < 0.01. (E) Western blot analysis of liver extracts from adenovirus-injected mice. (F) Effect of FoxO1 inhibition by siRNA on insulin-induced Akt phosphorylation. We transduced cells with adenovirus encoding control siRNA or FoxO1siRNA and immunoblotted with the indicated antibodies. (G) Effect of FoxO1 DNA binding–deficient transduction on insulin-induced Akt phosphorylation. All data are representative of at least 3 independent experiments.