Suppression of FoxO1 Activity by Long-Chain Fatty Acyl Analogs

  1. Jacob Bar-Tana1
  1. 1Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel
  2. 2Cardiovascular Research Center, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  3. 3Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
  1. Corresponding author: Jacob Bar-Tana, bartanaj{at}cc.huji.ac.il.
  1. G.Z. and R.H. contributed equally to this work.

Abstract

OBJECTIVE Overactivity of the Forkhead transcription factor FoxO1 promotes diabetic hyperglycemia, dyslipidemia, and acute-phase response, whereas suppression of FoxO1 activity by insulin may alleviate diabetes. The reported efficacy of long-chain fatty acyl (LCFA) analogs of the MEDICA series in activating AMP-activated protein kinase (AMPK) and in treating animal models of diabesity may indicate suppression of FoxO1 activity.

RESEARCH DESIGN AND METHODS The insulin-sensitizing and anti-inflammatory efficacy of a MEDICA analog has been verified in guinea pig and in human C-reactive protein (hCRP) transgenic mice, respectively. Suppression of FoxO1 transcriptional activity has been verified in the context of FoxO1- and STAT3-responsive genes and compared with suppression of FoxO1 activity by insulin and metformin.

RESULTS Treatment with MEDICA analog resulted in total body sensitization to insulin, suppression of lipopolysaccharide-induced hCRP and interleukin-6–induced acute phase reactants and robust decrease in FoxO1 transcriptional activity and in coactivation of STAT3. Suppression of FoxO1 activity was accounted for by its nuclear export by MEDICA-activated AMPK, complemented by inhibition of nuclear FoxO1 transcriptional activity by MEDICA-induced C/EBPβ isoforms. Similarly, insulin treatment resulted in nuclear exclusion of FoxO1 and further suppression of its nuclear activity by insulin-induced C/EBPβ isoforms. In contrast, FoxO1 suppression by metformin was essentially accounted for by its nuclear export by metformin-activated AMPK.

CONCLUSIONS Suppression of FoxO1 activity by MEDICA analogs may partly account for their antidiabetic anti-inflammatory efficacy. FoxO1 suppression by LCFA analogs may provide a molecular rational for the beneficial efficacy of carbohydrate-restricted ketogenic diets in treating diabetes.

Footnotes

    • Received February 24, 2011.
    • Accepted April 9, 2011.

    Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

    | Table of Contents

    This Article

    1. Diabetes vol. 60 no. 7 1872-1881
    1. All Versions of this Article:
      1. db11-0248v1
      2. 60/7/1872 most recent