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Suppression of FoxO1 activity by long-chain fatty acyl analogs
Ghadeer Zatara1, Rachel Hertz, Maayan Shaked
1Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel.
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.
Insights
MEDICA analogs suppress Forkhead transcription factor FoxO1 activity, alleviating diabetic hyperglycemia and inflammation. This mechanism, involving AMP-activated protein kinase (AMPK) and C/EBPβ, offers a potential therapeutic strategy for diabetes.
Area of Science:
- Molecular Biology
- Metabolic Diseases
- Pharmacology
Background:
- Overactive Forkhead transcription factor FoxO1 drives diabetic complications like hyperglycemia and inflammation.
- Insulin suppresses FoxO1 activity, suggesting therapeutic potential for diabetes management.
- Long-chain fatty acyl (LCFA) analogs of the MEDICA series activate AMP-activated protein kinase (AMPK), hinting at FoxO1 suppression capabilities.
Purpose of the Study:
- To investigate the insulin-sensitizing and anti-inflammatory effects of a MEDICA analog.
- To verify the suppression of FoxO1 transcriptional activity by MEDICA analogs.
- To compare the mechanism of FoxO1 suppression by MEDICA analogs with insulin and metformin.
Main Methods:
- Assessed insulin-sensitizing effects in guinea pigs and anti-inflammatory effects in human C-reactive protein (hCRP) transgenic mice.
- Quantified suppression of FoxO1 and STAT3-responsive genes.
- Compared FoxO1 activity suppression with insulin and metformin treatments.
Main Results:
- MEDICA analog treatment enhanced insulin sensitivity and suppressed inflammatory markers (hCRP, IL-6).
- MEDICA analogs robustly decreased FoxO1 transcriptional activity and STAT3 coactivation.
- FoxO1 nuclear export via AMPK and C/EBPβ inhibition by MEDICA contributed to suppressed activity, similar to insulin and metformin.
Conclusions:
- MEDICA analog-induced suppression of FoxO1 activity partially explains their antidiabetic and anti-inflammatory benefits.
- Targeting FoxO1 with LCFA analogs provides a molecular basis for the efficacy of ketogenic diets in diabetes treatment.
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