TY - JOUR
T1 - Downregulation of PGC-1α prevents the beneficial effect of EET-heme oxygenase-1 on mitochondrial integrity and associated metabolic function in obese mice
AU - Singh, Shailendra P.
AU - Bellner, Lars
AU - Vanella, Luca
AU - Cao, Jian
AU - Falck, J R
AU - Kappas, Attallah
AU - Abraham, Nader G.
N1 - Funding Information:
This work was supported by National Institutes of Health Grants HL34300 and HL55601, the Brickstreet Foundation, the Huntington Foundation (Nader G. Abraham), and gifts from the Renfield Foundation to The Rockefeller University (Attallah Kappas). The authors wish to thank Dr. G. Drummond for his excellent reviewing of the scientific content andMrs. Jennifer Brown,Department of Pharmacology,New YorkMedical College, for her outstanding editorial assistance in the preparation of the manuscript.
Publisher Copyright:
Copyright © 2016 Shailendra P. Singh et al.
PY - 2016
Y1 - 2016
N2 - 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. Culturedmurine adipocytes and mice fed a high fat (HF) dietwere used to assess the functional relationship among EETs, PGC-1α,HO-1, andmitochondrial signaling using an EET-agonist (EET-A) and PGC-1α-deficient cells and mice using lentiviral PGC-1α(sh). Results. EET-Ais 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 preventedHF 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.
AB - 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. Culturedmurine adipocytes and mice fed a high fat (HF) dietwere used to assess the functional relationship among EETs, PGC-1α,HO-1, andmitochondrial signaling using an EET-agonist (EET-A) and PGC-1α-deficient cells and mice using lentiviral PGC-1α(sh). Results. EET-Ais 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 preventedHF 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.
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U2 - 10.1155/2016/9039754
DO - 10.1155/2016/9039754
M3 - Article
C2 - 28097021
AN - SCOPUS:85008683536
SN - 2090-0724
VL - 2016
JO - Journal of Nutrition and Metabolism
JF - Journal of Nutrition and Metabolism
M1 - 9039754
ER -