Epoxygenase inactivation exacerbates diet and aging-associated metabolic dysfunction resulting from impaired adipogenesis

Objective : W hen molecular drivers of healthy adipogenesis are perturbed, this can cause hepatic steatosis . The role of arachidonic acid (AA) and its downstream enzymatic cascades such as cyclooxygenase in adipogenesis is well established while the exact contribution of P450 epoxygenase pathway remain to be established. Enzymes belonging to this pathway are mainly encoded by the CYP2J locus but the latter shows extensive allelic expansion in mice , an obstacle for adipogenesis -related studies . The human CYP2J locus cont ains a single gene (CYP2J2) whereas mice and rats have 8 and 3 paralogues, respectively. Methods and results : We took advantage of the simpler genetic architecture of the Cyp2j locus in the rat and generated a Cyp2j4 (orthologue of human CYP2J2 ) knockout rat . We used Cyp2j4 - /- rats in two models of metabolic dysfunction: physiological aging and cafeteria diet (CAF). The phenotyping of Cyp2j4 - /- rats under CAF was integrated with proteomics (LC - MS/MS ) and lipidomics (LC -MS) analyses in the liver and the adi pose tissue. We report that Cyp2j4 deletion causes adipocyte dysfunction under metabolic challenges. This is characterised by (i) down- regulation of white adipose tissue (WAT) PPARγ and C/EBPα , (ii) adipocyte hypertrophy (iii) extracellular matrix remodelling and (iv) alternative usage of AA pathway . Specifically, in Cyp2j4 -/- rats treated with a cafeteria diet, the dysfunctional adipogenesis is accompanied by exacerbated weight gain, hepatic lipid ac cumulation and dysregulated gluconeogenesis . Conclusion : These results suggest that AA epoxygenases are essential regulat ors of healthy adipogenesis. Our results uncover their synergistic role in fine -tuning AA pathway in obesity -mediated hepatic steatosis