RGD Reference Report - Epoxygenase inactivation exacerbates diet and aging-associated metabolic dysfunction resulting from impaired adipogenesis. - Rat Genome Database

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

Authors: Olona, Antoni  Terra, Ximena  Ko, Jeong-Hun  Grau-BovĂ©, Carme  Pinent, Montserrat  Ardevol, Anna  Diaz, Ana Garcia  Moreno-Moral, Aida  Edin, Matthew  Bishop-Bailey, David  Zeldin, Darryl C  Aitman, Timothy J  Petretto, Enrico  Blay, Mayte  Behmoaras, Jacques 
Citation: Olona A, etal., Mol Metab. 2018 May;11:18-32. doi: 10.1016/j.molmet.2018.03.003. Epub 2018 Mar 9.
RGD ID: 150520032
Pubmed: PMID:29656108   (View Abstract at PubMed)
PMCID: PMC6001407   (View Article at PubMed Central)
DOI: DOI:10.1016/j.molmet.2018.03.003   (Journal Full-text)

OBJECTIVE: When 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. The exact contribution of the P450 epoxygenase pathway, however, remains to be established. Enzymes belonging to this pathway are mainly encoded by the CYP2J locus which shows extensive allelic expansion in mice. Here we aimed to establish the role of endogenous epoxygenase during adipogenesis under homeostatic and metabolic stress conditions.
METHODS: We took advantage of the simpler genetic architecture of the Cyp2j locus in the rat and used a Cyp2j4 (orthologue of human CYP2J2) knockout rat 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 adipose tissue.
RESULTS: We report that Cyp2j4 deletion causes adipocyte dysfunction under metabolic challenges. This is characterized by (i) down-regulation of white adipose tissue (WAT) PPARγ and C/EBPα, (ii) adipocyte hypertrophy, (iii) extracellular matrix remodeling, 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 accumulation, and dysregulated gluconeogenesis.
CONCLUSION: These results suggest that AA epoxygenases are essential regulators of healthy adipogenesis. Our results uncover their synergistic role in fine-tuning AA pathway in obesity-mediated hepatic steatosis.

Objects Annotated

Genes (Rattus norvegicus)
Cyp2j4  (cytochrome P450, family 2, subfamily j, polypeptide 4)
Cyp2j4em1Sage  (cytochrome P450, family 2, subfamily j, polypeptide 4, ZFN induced mutant 1, Sage)

WKY-Cyp2j4em1Sage/Tja  (NA)

Additional Information