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 2

FoxO1ADA promotes Akt activation independent of increased Irs2 expression.

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FoxO1ADA promotes Akt activation independent of increased Irs2 expressio...
(A and B) Effects of FoxO1ADA in SV40-transformed hepatocytes transduced with FoxO1ADA at different MOIs. We incubated cells with insulin for 10 minutes and subjected cell lysates to immunoblot analysis with the indicated antibodies. All data are representative of at least 3 independent experiments. Fao hepatoma cells transduced with FoxO1ADA (C) or Irs2 (D) adenovirus were preincubated for 24 hours in the absence or presence of insulin. For immunoprecipitation, cells were treated for 2 minutes with insulin, and lysates were immunoprecipitated with antibodies against Irs2 and immunoblotted with either anti-phosphotyrosine or anti-Irs2 antibodies. For direct immunoblot analysis, the immunoprecipitation step was omitted. All data are representative of at least 2 independent experiments. (E) C2C12 myotubes transduced with FoxO1ADA adenovirus were incubated with insulin for 10 minutes and analyzed by direct immunoblotting with the indicated antibodies or immunoprecipitated and immunoblotted with antibodies to either Irs1 or Irs2.