title: Downregulation of PGC-1αPrevents the Beneficial Effect of EET-Heme Oxygenase-1 on Mitochondrial Integrity and Associated Metabolic Function in Obese Mice.
abstract: 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-1αin 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 VO2effects that were abrogated in PGC-1α-deficient mice.Conclusion. EET is identified as an upstream positive regulator of PGC-1αthat 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.
authors.affiliation: New York Medical College, Departments of Medicine and Pharmacology, Valhalla, NY, USA.
authors.forename: Shailendra P
authors.initials: SP
authors.lastname: Singh
authors.affiliation: New York Medical College, Departments of Medicine and Pharmacology, Valhalla, NY, USA.
authors.forename: Lars
authors.initials: L
authors.lastname: Bellner
authors.affiliation: New York Medical College, Departments of Medicine and Pharmacology, Valhalla, NY, USA; Department of Drug Science, Section of Biochemistry, University of Catania, Catania, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Vanella
authors.affiliation: First Geriatric Cardiology Division, Chinese PLA General Hospital, Beijing, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Cao
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.affiliation: The Rockefeller University, New York, NY, USA.
authors.forename: Attallah
authors.initials: A
authors.lastname: Kappas
authors.affiliation: New York Medical College, Departments of Medicine and Pharmacology, Valhalla, NY, USA; The Rockefeller University, New York, NY, USA.
authors.forename: Nader G
authors.identifier: 0000-0001-8983-1959
authors.initials: NG
authors.lastname: Abraham