title: Characterization of Eicosanoids Produced by Adipocyte Lipolysis: IMPLICATION OF CYCLOOXYGENASE-2 IN ADIPOSE INFLAMMATION.
abstract: Excessive adipocyte lipolysis generates lipid mediators and triggers inflammation in adipose tissue. However, the specific roles of lipolysis-generated mediators in adipose inflammation remain to be elucidated. In the present study, cultured 3T3-L1 adipocytes were treated with isoproterenol to activate lipolysis and the fatty acyl lipidome of released lipids was determined by using LC-MS/MS. We observed that β-adrenergic activation elevated levels of approximately fifty lipid species, including metabolites of cyclooxygenases, lipoxygenases, epoxygenases, and other sources. Moreover, we found that β-adrenergic activation induced cyclooxygenase 2 (COX-2), not COX-1, expression in a manner that depended on activation of hormone-sensitive lipase (HSL) in cultured adipocytes and in the epididymal white adipose tissue (EWAT) of C57BL/6 mice. We found that lipolysis activates the JNK/NFκB signaling pathway and inhibition of the JNK/NFκB axis abrogated the lipolysis-stimulated COX-2 expression. In addition, pharmacological inhibition of COX-2 activity diminished levels of COX-2 metabolites during lipolytic activation. Inhibition of COX-2 abrogated the induction of CCL2/MCP-1 expression by β-adrenergic activation and prevented recruitment of macrophage/monocyte to adipose tissue. Collectively, our data indicate that excessive adipocyte lipolysis activates the JNK/NFκB pathway leading to the up-regulation of COX-2 expression and recruitment of inflammatory macrophages.
authors.affiliation: From the Bioactive Lipid Research Program, Department of Pathology.
authors.forename: Allison
authors.initials: A
authors.lastname: Gartung
authors.affiliation: From the Bioactive Lipid Research Program, Department of Pathology.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Zhao
authors.affiliation: From the Bioactive Lipid Research Program, Department of Pathology.
authors.forename: Simon
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Pathology.
authors.forename: Emilio
authors.initials: E
authors.lastname: Mottillo
authors.affiliation: Department of Chemistry.
authors.forename: Garrett C
authors.initials: GC
authors.lastname: VanHecke
authors.affiliation: Department of Chemistry.
authors.forename: Young-Hoon
authors.initials: YH
authors.lastname: Ahn
authors.affiliation: From the Bioactive Lipid Research Program, Department of Pathology.
authors.forename: Krishna Rao
authors.initials: KR
authors.lastname: Maddipati
authors.affiliation: Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
authors.forename: Andrey
authors.initials: A
authors.lastname: Sorokin
authors.affiliation: Center for Integrative Metabolic and Endocrine Research, Center for Molecular Medicine and Genetics.
authors.forename: James
authors.initials: J
authors.lastname: Granneman
authors.affiliation: From the Bioactive Lipid Research Program, Department of Pathology, Cardiovascular Research Institute, and Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48202 and menqjer.lee@wayne.edu.
authors.forename: Menq-Jer
authors.initials: MJ
authors.lastname: Lee
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D015777:Eicosanoids / Q000096:biosynthesis*; D007249:Inflammation / Q000201:enzymology / Q000473:pathology; D008066:Lipolysis; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D015434:Panniculitis / Q000201:enzymology* / Q000473:pathology; D015398:Signal Transduction; D002787:Sterol Esterase / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D015777:Eicosanoids; D016328:NF-kappa B; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048670:MAP Kinase Kinase 4; D002787:Sterol Esterase
keywords: NF-kappa B (NF-κB); adipocyte; adrenergic receptor; cyclooxygenase (COX); eicosanoid; inflammation; lipolysis; prostaglandin