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, how...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-05-01
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| Series: | Molecular Metabolism |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877818300711 |
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 Epoxygenase inactivation exacerbates diet and aging-associated metabolic dysfunction resulting from impaired adipogenesis Molecular Metabolism |
| author_facet |
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 |
| author_sort |
Antoni Olona |
| title |
Epoxygenase inactivation exacerbates diet and aging-associated metabolic dysfunction resulting from impaired adipogenesis |
| title_short |
Epoxygenase inactivation exacerbates diet and aging-associated metabolic dysfunction resulting from impaired adipogenesis |
| title_full |
Epoxygenase inactivation exacerbates diet and aging-associated metabolic dysfunction resulting from impaired adipogenesis |
| title_fullStr |
Epoxygenase inactivation exacerbates diet and aging-associated metabolic dysfunction resulting from impaired adipogenesis |
| title_full_unstemmed |
Epoxygenase inactivation exacerbates diet and aging-associated metabolic dysfunction resulting from impaired adipogenesis |
| title_sort |
epoxygenase inactivation exacerbates diet and aging-associated metabolic dysfunction resulting from impaired adipogenesis |
| publisher |
Elsevier |
| series |
Molecular Metabolism |
| issn |
2212-8778 |
| publishDate |
2018-05-01 |
| description |
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 |
| url |
http://www.sciencedirect.com/science/article/pii/S2212877818300711 |
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doaj-d7285575e91349bf8008e12a518b25d12020-11-24T22:55:54ZengElsevierMolecular Metabolism2212-87782018-05-01111832Epoxygenase inactivation exacerbates diet and aging-associated metabolic dysfunction resulting from impaired adipogenesisAntoni Olona0Ximena Terra1Jeong-Hun Ko2Carme Grau-Bové3Montserrat Pinent4Anna Ardevol5Ana Garcia Diaz6Aida Moreno-Moral7Matthew Edin8David Bishop-Bailey9Darryl C. Zeldin10Timothy J. Aitman11Enrico Petretto12Mayte Blay13Jacques Behmoaras14Centre for Complement and Inflammation Research, Imperial College London, London, W12 0NN, UKCentre for Complement and Inflammation Research, Imperial College London, London, W12 0NN, UK; Mobiofood Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, 43007, Tarragona, SpainCentre for Complement and Inflammation Research, Imperial College London, London, W12 0NN, UKCentre for Complement and Inflammation Research, Imperial College London, London, W12 0NN, UK; Mobiofood Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, 43007, Tarragona, SpainMobiofood Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, 43007, Tarragona, SpainMobiofood Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, 43007, Tarragona, SpainRenal and Vascular Inflammation Section, Department of Medicine, Imperial College London, London, W12 0NN, UKDuke-NUS Medical School, National University of Singapore, 169857, SingaporeDivision of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USAComparative Biomedical Sciences, Royal Veterinary College, London, NW1 0TU, UKDivision of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USACentre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UKDuke-NUS Medical School, National University of Singapore, 169857, SingaporeMobiofood Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, 43007, Tarragona, SpainCentre for Complement and Inflammation Research, Imperial College London, London, W12 0NN, UK; Corresponding author. Centre for Complement and Inflammation Research (CCIR), Imperial College London Hammersmith Hospital, Du Cane Road, W12 0NN, London, UK.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 acidhttp://www.sciencedirect.com/science/article/pii/S2212877818300711 |