title: Functional characterization of cytochrome P450-derived epoxyeicosatrienoic acids in adipogenesis and obesity.
abstract: Adipogenesis plays a critical role in the initiation and progression of obesity. Although cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) have emerged as a potential therapeutic target for cardiometabolic disease, the functional contribution of EETs to adipogenesis and the pathogenesis of obesity remain poorly understood. Our studies demonstrated that induction of adipogenesis in differentiated 3T3-L1 cells (in vitro) and obesity-associated adipose expansion in high-fat diet (HFD)-fed mice (in vivo) significantly dysregulate the CYP epoxygenase pathway and evoke a marked suppression of adipose-derived EET levels. Subsequent in vitro experiments demonstrated that exogenous EET analog administration elicits potent anti-adipogenic effects via inhibition of the early phase of adipogenesis. Furthermore, EET analog administration to mice significantly mitigated HFD-induced weight gain, adipose tissue expansion, pro-adipogenic gene expression, and glucose intolerance. Collectively, these findings suggest that suppression of EET bioavailability in adipose tissue is a key pathological consequence of obesity, and strategies that promote the protective effects of EETs in adipose tissue offer enormous therapeutic potential for obesity and its downstream pathological consequences.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC.
authors.forename: Weibin
authors.initials: W
authors.lastname: Zha
authors.affiliation: Laboratory of Respiratory Biology, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Edin
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC.
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Vendrov
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Schuck
authors.affiliation: Laboratory of Respiratory Biology, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
authors.forename: Fred B
authors.initials: FB
authors.lastname: Lih
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Jawahar Lal
authors.initials: JL
authors.lastname: Jat
authors.affiliation: Laboratory of Respiratory Biology, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
authors.forename: J Alyce
authors.initials: JA
authors.lastname: Bradbury
authors.affiliation: Laboratory of Respiratory Biology, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
authors.forename: Laura M
authors.initials: LM
authors.lastname: DeGraff
authors.affiliation: UNC Nutrition Obesity Research Center, University of North Carolina, Chapel Hill, NC.
authors.forename: Kunjie
authors.initials: K
authors.lastname: Hua
authors.affiliation: Laboratory of Respiratory Biology, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Tomer
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.affiliation: Laboratory of Respiratory Biology, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Lee
mesh_terms: D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D003577:Cytochrome P-450 Enzyme System; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects; D015777:Eicosanoids / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D018149:Glucose Intolerance / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D004041:Dietary Fats; D015777:Eicosanoids; D003577:Cytochrome P-450 Enzyme System
keywords: adipose tissue; arachidonic acid; eicosanoids; high-fat diet; metabolomics; soluble epoxide hydrolase
references.citation: FASEB J. 2011 Feb;25(2):703-13
references.pmid: 21059750
references.citation: FASEB J. 2011 Oct;25(10):3436-47
references.pmid: 21697548
references.citation: Curr Protoc Toxicol. 2007;Chapter 4:Unit 4.23
references.pmid: 23045145
references.citation: Am J Physiol Endocrinol Metab. 2012 Mar 1;302(5):E500-9
references.pmid: 22185841
references.citation: FASEB J. 2013 Aug;27(8):2946-56
references.pmid: 23603837
references.citation: Am J Physiol Heart Circ Physiol. 2007 Jul;293(1):H142-51
references.pmid: 17322420
references.citation: Dis Model Mech. 2010 Sep-Oct;3(9-10):525-34
references.pmid: 20713647
references.citation: Cell Res. 2008 Feb;18(2):311-23
references.pmid: 18195731
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Nucleic Acids Res. 2012 Jul;40(Web Server issue):W127-33
references.pmid: 22553367
references.citation: J Mol Cell Cardiol. 2010 Feb;48(2):331-41
references.pmid: 19891972
references.citation: Cell Physiol Biochem. 2012;29(1-2):99-110
references.pmid: 22415079
references.citation: Diabetes. 2011 Oct;60(10):2474-83
references.pmid: 21911747
references.citation: Mol Pharmacol. 2004 May;65(5):1148-58
references.pmid: 15102943
references.citation: Biochem J. 2003 Nov 1;375(Pt 3):539-49
references.pmid: 18320708
references.citation: Proc Natl Acad Sci U S A. 2011 May 31;108(22):9038-43
references.pmid: 21571638
references.citation: Annu Rev Biochem. 1995;64:345-73
references.pmid: 7574486
references.citation: Adipocyte. 2013 Jul 1;2(3):160-4
references.pmid: 23991362
references.citation: Atherosclerosis. 2012 Jun;222(2):530-6
references.pmid: 22503544
references.citation: Physiol Rev. 2012 Jan;92(1):101-30
references.pmid: 22298653
references.citation: Diabetes. 2012 Sep;61(9):2311-9
references.pmid: 22688342
references.citation: PLoS One. 2013;8(3):e59514
references.pmid: 23533630
references.citation: J Clin Invest. 2011 Jun;121(6):2094-101
references.pmid: 21633177
references.citation: Am J Physiol Renal Physiol. 2006 Jul;291(1):F155-61
references.pmid: 16478979
references.citation: Front Physiol. 2010 Dec 03;1:157
references.pmid: 21423396
references.citation: Am J Physiol Endocrinol Metab. 2009 Dec;297(6):E1378-87
references.pmid: 19808909
references.citation: Drug Metab Dispos. 2011 Jan;39(1):22-9
references.pmid: 20947618
references.citation: J Biol Chem. 2013 May 17;288(20):14189-14199
references.pmid: 23576437
references.citation: Prostaglandins Other Lipid Mediat. 2012 Aug;98(3-4):133-42
references.pmid: 22209722
references.citation: Am J Physiol Endocrinol Metab. 2011 Jun;300(6):E1124-34
references.pmid: 21427413
references.citation: Mol Endocrinol. 2002 Nov;16(11):2628-44
references.pmid: 12403851
references.citation: Nat Med. 2013 Oct;19(10):1338-44
references.pmid: 23995282
references.citation: J Biol Chem. 2001 Jul 6;276(27):25467-79
references.pmid: 11328810
references.citation: Prostaglandins Other Lipid Mediat. 2011 Nov;96(1-4):54-62
references.pmid: 21821145
references.citation: Am J Physiol Regul Integr Comp Physiol. 2005 Jan;288(1):R188-96
references.pmid: 15345471
references.citation: Genes Dev. 2000 Jun 1;14(11):1293-307
references.pmid: 10837022
references.citation: Physiol Rev. 2004 Jan;84(1):277-359
references.pmid: 14715917
references.citation: Obesity (Silver Spring). 2010 Mar;18(3):489-98
references.pmid: 19644452
references.citation: J Biol Chem. 2000 Dec 22;275(51):40504-10
references.pmid: 11001943
references.citation: J Biol Chem. 2011 Jan 7;286(1):889-98
references.pmid: 20961858
references.citation: Biochem Biophys Res Commun. 2006 Feb 3;340(1):43-7
references.pmid: 16377306
references.citation: Science. 2013 Jan 11;339(6116):172-7
references.pmid: 23307735
references.citation: Diabetes. 2013 Jun;62(6):1774-82
references.pmid: 23704518
references.citation: JAMA. 2012 Feb 1;307(5):491-7
references.pmid: 22253363
references.citation: J Clin Invest. 2001 Oct;108(7):1001-13
references.pmid: 11581301
references.citation: PLoS One. 2010 Feb 09;5(2):e9069
references.pmid: 20161729
references.citation: Stem Cells Dev. 2010 Dec;19(12):1863-73
references.pmid: 20412023
references.citation: J Biol Chem. 2001 Sep 28;276(39):36059-62
references.pmid: 11451964
references.citation: Diabetes. 2010 Apr;59(4):997-1005
references.pmid: 20068141