The growing prevalence of obesity and type 2 diabetes complicates risk and clinical management by potentiating and/or exacerbating hypertension, hyperlipidemia, atherosclerosis and cardiomyopathy, leading to increasing use of the term “cardiometabolic disease” (CMD) to encompass the many facets of this complex syndrome. The inventors assessed the role of the soluble epoxide hydrolase (she) phosphatase domain in metabolism and cardiovascular system, by generating sEH phosphatase knock-in (KI) animals (rats). They unexpectedly revealed that inhibition of the phosphatase domain of sEH could improve cardiac systolic function, decrease body weight, increase insulin sensitivity. More over under high fat diet, the animals have a decreased body weight gain, were protected against the development of insulin resistance, hepatic steatosis and cardiac hypertrophy. Inhibition of the phosphatase domain of sEH could thus represent a new pharmacological target in the treatment of cardiometabolic diseases.