Question:

The cytochrome P450 (CYP) epoxygenases and soluble epoxide hydrolase (sEH) enzymes generate lipid mediators (fatty acid epoxides and diols) that are involved in the regulation of blood pressure. Recent reports indicate that sEH inhibition affects glucose homeostasis and that sEH expression is increased in obesity. In this study we evaluated the impact of altered sEH expression on obesity-induced insulin resistance and hypertension.

Methods:

Wild-type mice, global sEH knockout (sEH^-/-) mice and mice lacking the sEH enzyme in adipocytes (Fabp4-sEH^-/-) were fed either normal chow or a high-fat diet.

Results:

The high-fat diet induced obesity in wild-type mice (body mass index or BMI: 4.6±0.2 kg/m²), sEH^-/- mice (BMI: 5.7±0.3 kg/m²) and Fabp4-sEH^-/- mice (BMI: 5.0±0.2 kg/m²) and increased systolic blood pressure in wild-type mice (148±18 mmHg) but not in sEH^-/- or Fabp4-sEH mice (94±6 and 102±20 mmHg, respectively). Wild-type mice fed the high-fat diet developed manifest diabetes (blood glucose levels 2 hours after glucose application >200 mg/dL), while the sEH^-/- mice were protected. Interestingly, Fabp4-sEH^-/- were not protected from impaired glucose tolerance and developed adipocyte hypertrophy and liver steatosis.

Conclusion:

Thus although the global inhibition of sEH activity protects against the development of diet-induced diabetes and hypertension it seems that the sEH in distinct cell types/tissues contributes to different aspects of disease development.