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Epoxides Attenuate Adipogenesis in human Mesenchymal Stem Cells via Activation of Heme Oxygenase‐Adiponectin Pathways

The cytochrome P450 ‐ derived epoxyeicosatrienoic acids (EETs) represent a lipid mediator with cyto‐protective and anti‐apoptotic properties. Human mesenchymal stem cells (MSCs) express CYP450 class of enzymes their ability to form epoxides and their effect on MSC derived adipogenesis has not been characterized. We investigated and now show that human MSCs express CYP2J2 involved in EET formation, along with significant levels. Inhibition of EET degradation and/or agonism by 12‐(3‐hexylureido)dodec‐8(Z)‐enoic acid in adipocytes demonstrated an increase in number of small healthy adipocytes, and reduction in lipid accumulation (p<0.05). These effects were accompanied by increased levels of HO‐1 and adiponectin (p<0.05). Also, EET agonist reduced the total number of adipocytes in a dose dependent manner with EETs having the maximum effect. Inhibition of HO activity prevented EET‐induced inhibition of adipogenesis, along with bringing about a reduction in the levels of adiponectin. Our results suggest that epoxides decrease MSCs‐derived adipogenesis by up regulating HO‐1‐adiponectin pathways and play a central role in the regulation of adipocyte differentiation. In conclusion, these novel findings highlight the seminal role of arachidonic acid metabolism in MSCs and suggest that an EET‐agonist may have therapeutic potential in the treatment of dyslipidemia, diabetes and the metabolic syndrome.