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Mapping the fructose‐2,6‐bisphosphate signaling pathway
Author(s) -
Khan Salmaan Ahmed,
Wu Chaodong,
Peng LiJen,
Lange Alex J.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a959-d
Subject(s) - protein kinase b , adipose tissue , endocrinology , medicine , foxo1 , phosphorylation , insulin receptor , glut4 , fructose 2,6 bisphosphate , chemistry , allosteric regulation , fructose , biology , insulin , glycolysis , microbiology and biotechnology , insulin resistance , receptor , biochemistry , metabolism , phosphofructokinase
Modulation of fructose‐2,6‐bisphosphate (F‐2,6‐P 2 ) levels in the liver has been shown to correct the diabetic phenotype in type I and type II diabetes mouse models (streptozotocin‐treated and KK/H1J mice, respectively). The mechanism behind this nutrient‐derived molecule's ability is not limited to its allosteric effects on key glycolytic and gluconeogenic enzymes. We have determined that increasing hepatic F‐2,6‐P 2 activates insulin signaling components, as evidenced by an increase in Akt phosphorylation (~3‐fold). Furthermore, this increase in hepatic F‐2,6‐P 2 levels also increases Akt phosphorylation in adipose tissue 2‐fold, likely via inter‐tissue communication. Elevation of F‐2,6‐P 2 within the adipocyte itself also leads to increased Akt phosphorylation, suggesting that inter‐tissue communication from the liver to the adipose involves regulation of adipose F‐2,6‐P 2 content. To further characterize the insulinomimetic effect observed in the liver as well as the peripheral effect seen in adipose, we examined direct targets downstream of Akt in both tissues upon hepatic F‐2,6‐P 2 modulation. In the liver we examined the activity and nuclear localization of the forkhead transcription factor FOXO1 subject to hepatic F‐2,6‐P 2 manipulation, as this is one of the direct targets of Akt. With similar hepatic F‐2,6‐P 2 elevation, we also examined GLUT4 translocation ‐ an event under direct control of Akt and insulin signaling in adipose tissue. The evidence described here serves to strengthen the argument that F‐2,6‐P 2 regulates whole body glucose homeostasis by a mechanism that functions through insulin signaling to regulate targets both in liver and adipose tissue.