Exploring the structure-activity relationship of various sEH inhibitors in promoting brown adipogenesis

Background: Brown adipose tissue has emerged as a novel target for obesity prevention and treatment due to its responsibility for heat production. Soluble epoxide hydrolase (sEH) is a cytosolic enzyme that degrades epoxy fatty acids (EpFAs) (lipid signaling molecules) into inactive diols. Potent sEH inhibitors (sEHIs) are beneficial for many chronic diseases as they stabilize endogenous EpFAs by blocking the degradation. Our preliminary results have shown that trans-4- [4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), a potent sEH inhibitor, dose-dependently promotes brown adipogenesis.

Objectives: The objective of this study is to investigate the structure and activity relationship of various sEHIs with different sub-structures of t-AUCB to identify the structure properties that make t-AUCB a potent drug to promote brown adipogenesis.

Methods: Various doses of different sEHIs with modifications on the adamantane or benzoic acid groups of t-AUCB were added to the brown differentiation process. Brown adipogenesis was assessed by Oil Red O stained lipid accumulation and absorbance.

Results & Conclusion: There was a clear structure-activity relationship among the tested sEHIs. sEHI 1471-core (t-AUCB without benzoic acid), but not other tested sEHIs, significantly increased lipid accumulation. Further study on gene expression of brown adipocyte markers is needed to confirm the results of the lipids accumulation.