Obesity is a global epidemic and a common risk factor for endothelial dysfunction, and subsequent development of diabetes and vascular diseases such as hypertension. Epoxyeicosatrienoic acids (EETs) are cytochrome P450 (CYP)-derived metabolites of arachidonic acid and significantly contribute to vascular protection via stimulating vasodilation and inhibiting inflammation. Heme oxygenase-1 (HO-1) is a stress response protein that plays an important cytoprotective role against oxidative insult in diabetes and cardiovascular diseases. We recently demonstrated that crosstalk between EETs and HO-1 can attenuate adipogenesis. In the current study, we examined the hypothesis that adipocyte dysfunction in mice fed a high-fat (HF) diet can be prevented by endothelial-specific targeting of a human epoxygenase, CYP2J2, in transgenic mice. Tie2-CYP2J2 transgenic mice fed HF diets displayed significantly reduced visceral fat, blood glucose, inflammatory markers and blood pressure (from 126±4.1 to 102± 3.2 mmHg, p<0.05), and improved vascular function (maximum relaxation to acetylcholine from 61±7 to 90±6%, p<0.05) when compared to HF diet-fed wild type mice. Likewise, Tie2-CYP2J2 gene targeting restored HF-mediated decreases in vascular HO-1, peNOS, pAKT, and pAMPK protein expression. These changes translated into increased HO-1 and decreased inflammation within adipose tissue (adipose CD68 stained regions were reduced from 4.45±0.97 to 1.47±0.21%, p<0.05), coupled with decreased PPAR, C/EBPα, Mest, and aP2 expression, reflecting the systemic effect of EET overproduction on adipogenesis. We report that increased endothelial EET generation significantly attenuates HF diet-mediated adiposity and vascular dysfunction. Furthermore, our findings implicate crosstalk between EETs and HO-1 as an important cytoprotective mechanism to ameliorate vascular and adipocyte dysfunction resulting from diet-induced obesity.