• 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

Abraham

Abreu-Vieira

Behmoaras

Brons

Crewe

Cristancho

Darlington

Dennis

du Plessis

Farmer

Fleming

Forman

Fujiki

Fujimori

Giordano

Imig

Inceoglu

Khan

Kliewer

Kusminski

Lefterova

Luria

Mariman

Martinez-Micaelo

Medina-Gomez

Morisseau

Nadler

Odegaard

Otero

Palmer

Panigrahy

Pellegrinelli

Rosen

Sampey

Schafer

Scherer

Semple

Serhan

Soccio

Tanaka

Tontonoz

Uccelli

Umek

van der Poorten

Voigt

Waldman

Wamberg

Wang

Wernstedt Asterholm

Yaghootkar

Zeldin

Zhang

Zhou

Molecular Metabolism

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 aci

Antoni Olona

Ximena Terra

Jeong-Hun Ko

Carme Grau-Bové

Montserrat Pinent

Anna Ardevol

Ana Garcia Diaz

Aida Moreno-Moral

Matthew Edin

David Bishop-Bailey

Darryl C. Zeldin

Timothy J. Aitman

Enrico Petretto

Mayte Blay

Jacques Behmoaras

Directory of Open Access Journals

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

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.</p

Olona, Antoni

Terra, Ximena

Ko, Jeong-Hun

Grau-Bové, 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

Edinburgh Research Explorer

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

Olona, A

Terra, X

Ko, JH

Grau-Bove, C

Pinent, M

Ardevol, A

Garcia Diaz, A

Moreno-Moral, A

Edin, M

Bishop-Bailey, D

Zeldin, DC

Aitman, TJ

Petretto, E

Blay, M

Behmoaras, JV

Spiral - Imperial College Digital Repository

English

Crossref

Ko, J-H

Grau-Bové, C

Diaz, A G

Zeldin, D C

Aitman, T J

Behmoaras, J

RVC Research Online

• 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

RVC Repository (Royal Veterinary College)

https://rvc-repository.worktribe.com/preview/1388168/11255.pdf

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

Abstract

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Directory of Open Access Journals

Edinburgh Research Explorer

Spiral - Imperial College Digital Repository

Crossref

RVC Research Online

RVC Repository (Royal Veterinary College)

Edinburgh Research Explorer