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Downregulation of PGC-1α Prevents the Beneficial Effect of EET-Heme Oxygenase-1 on Mitochondrial Integrity and Associated Metabolic Function in Obese Mice
Background/Objectives. Obesity and metabolic syndrome and associated adiposity are a systemic condition characterized by increased mitochondrial dysfunction, inflammation, and inhibition of antioxidant genes, HO-1, and EETs levels. We postulate that EETs attenuate adiposity by stimulating mitochondr...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi Publishing Corporation
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206458/ https://www.ncbi.nlm.nih.gov/pubmed/28097021 http://dx.doi.org/10.1155/2016/9039754 |
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author | Singh, Shailendra P. Bellner, Lars Vanella, Luca Cao, Jian Falck, John R. Kappas, Attallah Abraham, Nader G. |
author_facet | Singh, Shailendra P. Bellner, Lars Vanella, Luca Cao, Jian Falck, John R. Kappas, Attallah Abraham, Nader G. |
author_sort | Singh, Shailendra P. |
collection | PubMed |
description | Background/Objectives. Obesity and metabolic syndrome and associated adiposity are a systemic condition characterized by increased mitochondrial dysfunction, inflammation, and inhibition of antioxidant genes, HO-1, and EETs levels. We postulate that EETs attenuate adiposity by stimulating mitochondrial function and induction of HO-1 via activation of PGC-1α in adipose and hepatic tissue. Methods. Cultured murine adipocytes and mice fed a high fat (HF) diet were used to assess the functional relationship among EETs, PGC-1α, HO-1, and mitochondrial signaling using an EET-agonist (EET-A) and PGC-1α-deficient cells and mice using lentiviral PGC-1α(sh). Results. EET-A is a potent inducer of PGC-1α, HO-1, mitochondrial biogenesis (cytochrome oxidase subunits 1 and 4 and SIRT3), fusion proteins (Mfn 1/2 and OPA1) and fission proteins (DRP1 and FIS1) (p < 0.05), fasting glucose, BW, and blood pressure. These beneficial effects were prevented by administration of lenti-PGC-1α(sh). EET-A administration prevented HF diet induced mitochondrial and dysfunction in adipose tissue and restored VO(2) effects that were abrogated in PGC-1α-deficient mice. Conclusion. EET is identified as an upstream positive regulator of PGC-1α that leads to increased HO-1, decreased BW and fasting blood glucose and increased insulin receptor phosphorylation, that is, increased insulin sensitivity and mitochondrial integrity, and possible use of EET-agonist for treatment of obesity and metabolic syndrome. |
format | Online Article Text |
id | pubmed-5206458 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Hindawi Publishing Corporation |
record_format | MEDLINE/PubMed |
spelling | pubmed-52064582017-01-17 Downregulation of PGC-1α Prevents the Beneficial Effect of EET-Heme Oxygenase-1 on Mitochondrial Integrity and Associated Metabolic Function in Obese Mice Singh, Shailendra P. Bellner, Lars Vanella, Luca Cao, Jian Falck, John R. Kappas, Attallah Abraham, Nader G. J Nutr Metab Research Article Background/Objectives. Obesity and metabolic syndrome and associated adiposity are a systemic condition characterized by increased mitochondrial dysfunction, inflammation, and inhibition of antioxidant genes, HO-1, and EETs levels. We postulate that EETs attenuate adiposity by stimulating mitochondrial function and induction of HO-1 via activation of PGC-1α in adipose and hepatic tissue. Methods. Cultured murine adipocytes and mice fed a high fat (HF) diet were used to assess the functional relationship among EETs, PGC-1α, HO-1, and mitochondrial signaling using an EET-agonist (EET-A) and PGC-1α-deficient cells and mice using lentiviral PGC-1α(sh). Results. EET-A is a potent inducer of PGC-1α, HO-1, mitochondrial biogenesis (cytochrome oxidase subunits 1 and 4 and SIRT3), fusion proteins (Mfn 1/2 and OPA1) and fission proteins (DRP1 and FIS1) (p < 0.05), fasting glucose, BW, and blood pressure. These beneficial effects were prevented by administration of lenti-PGC-1α(sh). EET-A administration prevented HF diet induced mitochondrial and dysfunction in adipose tissue and restored VO(2) effects that were abrogated in PGC-1α-deficient mice. Conclusion. EET is identified as an upstream positive regulator of PGC-1α that leads to increased HO-1, decreased BW and fasting blood glucose and increased insulin receptor phosphorylation, that is, increased insulin sensitivity and mitochondrial integrity, and possible use of EET-agonist for treatment of obesity and metabolic syndrome. Hindawi Publishing Corporation 2016 2016-12-20 /pmc/articles/PMC5206458/ /pubmed/28097021 http://dx.doi.org/10.1155/2016/9039754 Text en Copyright © 2016 Shailendra P. Singh et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Singh, Shailendra P. Bellner, Lars Vanella, Luca Cao, Jian Falck, John R. Kappas, Attallah Abraham, Nader G. Downregulation of PGC-1α Prevents the Beneficial Effect of EET-Heme Oxygenase-1 on Mitochondrial Integrity and Associated Metabolic Function in Obese Mice |
title | Downregulation of PGC-1α Prevents the Beneficial Effect of EET-Heme Oxygenase-1 on Mitochondrial Integrity and Associated Metabolic Function in Obese Mice |
title_full | Downregulation of PGC-1α Prevents the Beneficial Effect of EET-Heme Oxygenase-1 on Mitochondrial Integrity and Associated Metabolic Function in Obese Mice |
title_fullStr | Downregulation of PGC-1α Prevents the Beneficial Effect of EET-Heme Oxygenase-1 on Mitochondrial Integrity and Associated Metabolic Function in Obese Mice |
title_full_unstemmed | Downregulation of PGC-1α Prevents the Beneficial Effect of EET-Heme Oxygenase-1 on Mitochondrial Integrity and Associated Metabolic Function in Obese Mice |
title_short | Downregulation of PGC-1α Prevents the Beneficial Effect of EET-Heme Oxygenase-1 on Mitochondrial Integrity and Associated Metabolic Function in Obese Mice |
title_sort | downregulation of pgc-1α prevents the beneficial effect of eet-heme oxygenase-1 on mitochondrial integrity and associated metabolic function in obese mice |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206458/ https://www.ncbi.nlm.nih.gov/pubmed/28097021 http://dx.doi.org/10.1155/2016/9039754 |
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