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 4

FoxO1 suppresses Trb3 expression in an insulin-dependent manner.

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FoxO1 suppresses Trb3 expression in an insulin-dependent manner. Norther...
Northern blot analyses of Fao cells transduced with FoxO1ADA adenovirus and incubated with FSK-DEX and/or insulin for 20 hours (A); FoxO1ADA and Myr-p110 and treated with insulin in the absence or presence of LY294002 (LY) (B); FoxO1ADA and Myr-Akt and treated with or without insulin (C). 36b4 is a housekeeping gene used as a control for gel loading. (D) Hepatocytes transduced with FoxO1ADA (upper panel) or Irs2 (lower panel) adenoviruses were preincubated with insulin. Thereafter, cells were treated for 10 minutes with fresh insulin-containing medium, lysed, and immunoblotted with the indicated antibodies. All data are representative of at least 2 independent experiments. (E) Immunoblot analysis of the effect of cycloheximide on Trb3 expression. (F) Gene expression analysis by real-time RT-PCR in livers of control or FoxO1ADA mice (n = 6 for each). Each PCR was carried out in triplicate. *P < 0.05. (G) Western blot analysis of Trb3 expression in liver from control or FoxO1ADA mice. Northern blot and immunoblot data are representative of 3 independent experiments. (H) Northern blot analyses of Fao cells transduced with FoxO1ADA and Pgc1α.