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 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. copyright © 2016 shailendra p. singh et al.