Downregulation of PGC-1α prevents the beneficial effect of EET-heme oxygenase-1 on mitochondrial integrity and associated metabolic function in obese mice

Shailendra P. Singh, Lars Bellner, Luca Vanella, Jian Cao, J R Falck, Attallah Kappas, Nader G. Abraham

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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-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.

Original languageEnglish (US)
Article number9039754
JournalJournal of Nutrition and Metabolism
Volume2016
DOIs
StatePublished - 2016

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Food Science
  • Nutrition and Dietetics

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