Obesity is a global epidemic and a common risk factor for endothelial dysfunction and the subsequent development of diabetes mellitus and vascular diseases such as hypertension. Epoxyeicosatrienoic acids (EETs) are cytochrome P450 (CYP)–derived metabolites of arachidonic acid that contribute to vascular protection by stimulating vasodilation and inhibiting inflammation. Heme oxygenase-1 is a stress response protein that plays an important cytoprotective role against oxidative insult in diabetes mellitus and cardiovascular disease. We recently demonstrated interplay between EETs and heme oxygenase-1 in the attenuation of adipogenesis. We examined whether adipocyte dysfunction in mice fed a high-fat diet could be prevented by endothelial-specific targeting of the human CYP epoxygenase, CYP2J2. Tie2- CYP2J2 transgenic mice, fed a high-fat diet, had a reduction in body weight gain, blood glucose, insulin levels, and inflammatory markers. Tie2-CYP2J2 gene targeting restored HF-mediated decreases in vascular heme oxygenase-1, Cyp2C44, soluble epoxide hydrolase, phosphorylated endothelial nitric oxide synthase, phosphorylated protein kinase B, and phosphorylated adenosine monophosphate protein kinase protein expression, thus improving vascular function. These changes translated into decreased inflammation and oxidative stress within adipose tissue and decreased peroxisome proliferator–activated receptor-γ, CCAAT/enhancer binding protein alpha, mesoderm-specific transcript, and adipocyte 2 expression and increased uncoupling protein 1 and uncoupling protein 2 expression, reflecting the effect of vascular EET overproduction on adipogenesis. The current study documents a direct link between endothelial-specific EET production and adipogenesis, further implicating the EET-heme oxygenase-1 crosstalk as an important cytoprotective mechanism in the amelioration of vascular and adipocyte dysfunction resulting from diet-induced obesity.