Cargando…

Suppression of FoxO1 Activity by Long-Chain Fatty Acyl Analogs

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 a...

Descripción completa

Detalles Bibliográficos
Autores principales: Zatara, Ghadeer, Hertz, Rachel, Shaked, Maayan, Mayorek, Nina, Morad, Etedal, Grad, Etty, Cahan, Amos, Danenberg, Haim D., Unterman, Terry G., Bar-Tana, Jacob
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121436/
https://www.ncbi.nlm.nih.gov/pubmed/21602511
http://dx.doi.org/10.2337/db11-0248
_version_ 1782206823384743936
author Zatara, Ghadeer
Hertz, Rachel
Shaked, Maayan
Mayorek, Nina
Morad, Etedal
Grad, Etty
Cahan, Amos
Danenberg, Haim D.
Unterman, Terry G.
Bar-Tana, Jacob
author_facet Zatara, Ghadeer
Hertz, Rachel
Shaked, Maayan
Mayorek, Nina
Morad, Etedal
Grad, Etty
Cahan, Amos
Danenberg, Haim D.
Unterman, Terry G.
Bar-Tana, Jacob
author_sort Zatara, Ghadeer
collection PubMed
description 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.
format Online
Article
Text
id pubmed-3121436
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher American Diabetes Association
record_format MEDLINE/PubMed
spelling pubmed-31214362012-07-01 Suppression of FoxO1 Activity by Long-Chain Fatty Acyl Analogs Zatara, Ghadeer Hertz, Rachel Shaked, Maayan Mayorek, Nina Morad, Etedal Grad, Etty Cahan, Amos Danenberg, Haim D. Unterman, Terry G. Bar-Tana, Jacob Diabetes Metabolism 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. American Diabetes Association 2011-07 2011-06-20 /pmc/articles/PMC3121436/ /pubmed/21602511 http://dx.doi.org/10.2337/db11-0248 Text en © 2011 by the American Diabetes Association. 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.
spellingShingle Metabolism
Zatara, Ghadeer
Hertz, Rachel
Shaked, Maayan
Mayorek, Nina
Morad, Etedal
Grad, Etty
Cahan, Amos
Danenberg, Haim D.
Unterman, Terry G.
Bar-Tana, Jacob
Suppression of FoxO1 Activity by Long-Chain Fatty Acyl Analogs
title Suppression of FoxO1 Activity by Long-Chain Fatty Acyl Analogs
title_full Suppression of FoxO1 Activity by Long-Chain Fatty Acyl Analogs
title_fullStr Suppression of FoxO1 Activity by Long-Chain Fatty Acyl Analogs
title_full_unstemmed Suppression of FoxO1 Activity by Long-Chain Fatty Acyl Analogs
title_short Suppression of FoxO1 Activity by Long-Chain Fatty Acyl Analogs
title_sort suppression of foxo1 activity by long-chain fatty acyl analogs
topic Metabolism
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121436/
https://www.ncbi.nlm.nih.gov/pubmed/21602511
http://dx.doi.org/10.2337/db11-0248
work_keys_str_mv AT zataraghadeer suppressionoffoxo1activitybylongchainfattyacylanalogs
AT hertzrachel suppressionoffoxo1activitybylongchainfattyacylanalogs
AT shakedmaayan suppressionoffoxo1activitybylongchainfattyacylanalogs
AT mayoreknina suppressionoffoxo1activitybylongchainfattyacylanalogs
AT moradetedal suppressionoffoxo1activitybylongchainfattyacylanalogs
AT gradetty suppressionoffoxo1activitybylongchainfattyacylanalogs
AT cahanamos suppressionoffoxo1activitybylongchainfattyacylanalogs
AT danenberghaimd suppressionoffoxo1activitybylongchainfattyacylanalogs
AT untermanterryg suppressionoffoxo1activitybylongchainfattyacylanalogs
AT bartanajacob suppressionoffoxo1activitybylongchainfattyacylanalogs