title: Suppression of FoxO1 activity by long-chain fatty acyl analogs.
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.
  
  
  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.
authors: Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel.
authors: Ghadeer
authors: G
authors: Zatara
authors: Rachel
authors: R
authors: Hertz
authors: Maayan
authors: M
authors: Shaked
authors: Nina
authors: N
authors: Mayorek
authors: Etedal
authors: E
authors: Morad
authors: Etty
authors: E
authors: Grad
authors: Amos
authors: A
authors: Cahan
authors: Haim D
authors: HD
authors: Danenberg
authors: Terry G
authors: TG
authors: Unterman
authors: Jacob
authors: J
authors: Bar-Tana
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