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.