A. Cahan

Altomonte

Bar-Tana

Barthel

Besser

Bogojevi  

Bronner

Cheng

E. Grad

E. Morad

Emanuelli

Fernandez

Foretz

Foster

G. Zatara

H. D. Danenberg

J. Bar-Tana

Kalderon

Kamagate

Katz

Kirk

Kitamura

Leite

M. Shaked

Matsumoto

Mayorek

Meagher

Milosavljevi  

N. Mayorek

R. Hertz

Roberts

Russell

Samuel

Sheena

Silverman

Szalai

T. G. Unterman

van der Vos

Wang

Westman

Za'tara

Zhao

Zinszner

English

PubMed


                  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.
               </jats:sec

Ghadeer Zatara

Rachel Hertz

Maayan Shaked

Nina Mayorek

Etedal Morad

Etty Grad

Amos Cahan

Haim D. Danenberg

Terry G. Unterman

Jacob Bar-Tana

Crossref

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Suppression of FoxO1 Activity by Long-Chain Fatty Acyl Analogs

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