Elsevier

Molecular Metabolism

Volume 11, May 2018, Pages 18-32
Molecular Metabolism

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

https://doi.org/10.1016/j.molmet.2018.03.003Get rights and content
Under a Creative Commons license
open access

Highlights

  • Cyp2j4 deletion in rats offers a simplified genetic landscape as opposed to the mice locus, which is under significant allelic expansion.

  • Under different metabolic stresses (aging, cafeteria diet), Cyp2j4−/− rats show an accelerated adipogenesis, which progress towards adipocyte dysfunction.

  • Adipocyte dysfunction in Cyp2j4−/− rats under cafeteria diet (CAF) is characterised by down-regulation of white adipose tissue (WAT) PPARγ and C/EBPα, adipocyte hypertrophy and extracellular matrix remodeling.

  • Cyp2j4−/− rats treated with CAF display exacerbated weight gain, insulin resistance, hepatic lipid accumulation and dysregulated gluconeogenesis.

  • Cyp2j4−/− rats display alternative arachidonic acid pathway usage in their adipose tissue upon CAF and aging.

Abstract

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.

Keywords

Adipogenesis
Cytochrome P450 2j4
Cafeteria diet
Aging
Steatosis
Arachidonic acid

Abbreviations

WAT
white adipose tissue
PPAR-γ
peroxisome proliferator-activated receptor-γ
C/EBPα
CCAAT/enhancer binding protein-α
ECM
Extracellular Matrix
NAFLD
Non-alcoholic fatty liver diseases
Cyp
cytochrome P450
sEH
epoxide hydrolase
CAF
Cafeteria diet
EET
Epoxyeicosatrienoic acid
COX
Cyclooxygenase
LOX
Lipoxygenase
MSC
Mesenchymal Stromal Cells
SVF
Stromal Vascular Fraction
FASN
Fatty acid synthase gene

Cited by (0)

8

These authors contributed equally.