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...
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| Format: | Article |
| Language: | English |
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Wiley
2016-01-01
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| Series: | Journal of Nutrition and Metabolism |
| Online Access: | http://dx.doi.org/10.1155/2016/9039754 |
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| author | Shailendra P. Singh Lars Bellner Luca Vanella Jian Cao John R. Falck Attallah Kappas Nader G. Abraham |
| author_facet | Shailendra P. Singh Lars Bellner Luca Vanella Jian Cao John R. Falck Attallah Kappas Nader G. Abraham |
| author_sort | Shailendra P. Singh |
| collection | DOAJ |
| 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 VO2 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 | Article |
| id | doaj-art-244e23b59a694ae2b9c746c4307a704b |
| institution | Kabale University |
| issn | 2090-0724 2090-0732 |
| language | English |
| publishDate | 2016-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Nutrition and Metabolism |
| spelling | doaj-art-244e23b59a694ae2b9c746c4307a704b2025-02-03T07:24:46ZengWileyJournal of Nutrition and Metabolism2090-07242090-07322016-01-01201610.1155/2016/90397549039754Downregulation of PGC-1α Prevents the Beneficial Effect of EET-Heme Oxygenase-1 on Mitochondrial Integrity and Associated Metabolic Function in Obese MiceShailendra P. Singh0Lars Bellner1Luca Vanella2Jian Cao3John R. Falck4Attallah Kappas5Nader G. Abraham6New York Medical College, Departments of Medicine and Pharmacology, Valhalla, NY, USANew York Medical College, Departments of Medicine and Pharmacology, Valhalla, NY, USANew York Medical College, Departments of Medicine and Pharmacology, Valhalla, NY, USAFirst Geriatric Cardiology Division, Chinese PLA General Hospital, Beijing, ChinaDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USAThe Rockefeller University, New York, NY, USANew York Medical College, Departments of Medicine and Pharmacology, Valhalla, NY, USABackground/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 VO2 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.http://dx.doi.org/10.1155/2016/9039754 |
| spellingShingle | Shailendra P. Singh Lars Bellner Luca Vanella Jian Cao John R. Falck Attallah Kappas Nader G. Abraham Downregulation of PGC-1α Prevents the Beneficial Effect of EET-Heme Oxygenase-1 on Mitochondrial Integrity and Associated Metabolic Function in Obese Mice Journal of Nutrition and Metabolism |
| 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 |
| url | http://dx.doi.org/10.1155/2016/9039754 |
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