Previously we demonstrated that an EET‐agonist has pleiotropic effects including inhibition of Soluble Epoxide Hydrolase expression and reversed cardiomyopathy by decreasing inflammatory molecules and increasing antioxidant signaling. We hypothesized that an EET agonist would increase PGC‐1α, which controls mitochondrial function and HO‐1 induction and negatively regulates the expression of the proinflammatory adipokine NOV in both cardiac and pericardial tissues. This pathway would be expected to further improve left ventricular systolic function as well as increase insulin receptor phosphorylation. The effect of an EET agonist was measured in cardiac and pericardial adipose tissues in db/db mice on oxygen consumption, fractional shortening, blood glucose levels, thermogenic and mitochondrial signaling proteins. Control db/db mice developed signs of metabolic syndrome including insulin resistance, hypertension, inflammation, LV dysfunction, and increased NOV expression in pericardial adipose tissue. EET agonist decreased pericardial adipose tissue expression of NOV, normalized FS, increased PGC‐1α, HO‐1 levels, insulin receptor phosphorylation and improved mitochondrial function. HO‐1‐ derived carbon monoxide (CO) levels, mitochondrial function (p<0.01), insulin receptor phosphorylation (p<0.05), ATP levels and VO2 (p<0.05). Deletion of PGC‐1α reversed all of the above beneficial effects, increasing the expression of NOV and inflammatory cytokines in pericardial adipose tissue. These studies demonstrate that an EET agonist increases insulin receptor phosphorylation, mitochondrial and thermogenic gene expression, decreases cardiac and pericardial tissue NOV levels, and ameliorates cardiomyopathy in an obese mouse model of the metabolic syndrome. Further, this study demonstrated that EET‐mediated inhibition of NOV is a potential therapeutic target for the prevention of heart failure and the development of metabolic syndrome.Support or Funding InformationNational Institutes of Health grant (HL34300 to NGA)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.