Suppression of FoxO1 Activity by Long-Chain Fatty Acyl Analogs
- Ghadeer Zatara1,
- Rachel Hertz1,
- Maayan Shaked1,
- Nina Mayorek1,
- Etedal Morad1,
- Etty Grad2,
- Amos Cahan1,
- Haim D. Danenberg2,
- Terry G. Unterman3 and
- Jacob Bar-Tana1⇓
- 1Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel
- 2Cardiovascular Research Center, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
- 3Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
- Corresponding author: Jacob Bar-Tana, .
G.Z. and R.H. contributed equally to this work.
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.
- Received February 24, 2011.
- Accepted April 9, 2011.
- © 2011 by the American Diabetes Association.
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