title: Prostaglandin E2 Exerts Multiple Regulatory Actions on Human Obese Adipose Tissue Remodeling, Inflammation, Adaptive Thermogenesis and Lipolysis.
abstract: Obesity induces white adipose tissue (WAT) dysfunction characterized by unremitting inflammation and fibrosis, impaired adaptive thermogenesis and increased lipolysis. Prostaglandins (PGs) are powerful lipid mediators that influence the homeostasis of several organs and tissues. The aim of the current study was to explore the regulatory actions of PGs in human omental WAT collected from obese patients undergoing laparoscopic bariatric surgery. In addition to adipocyte hypertrophy, obese WAT showed remarkable inflammation and total and pericellular fibrosis. In this tissue, a unique molecular signature characterized by altered expression of genes involved in inflammation, fibrosis and WAT browning was identified by microarray analysis. Targeted LC-MS/MS lipidomic analysis identified increased PGE2 levels in obese fat in the context of a remarkable COX-2 induction and in the absence of changes in the expression of terminal prostaglandin E synthases (i.e. mPGES-1, mPGES-2 and cPGES). IPA analysis established PGE2 as a common top regulator of the fibrogenic/inflammatory process present in this tissue. Exogenous addition of PGE2 significantly reduced the expression of fibrogenic genes in human WAT explants and significantly down-regulated Col1α1, Col1α2 and αSMA in differentiated 3T3 adipocytes exposed to TGF-β. In addition, PGE2 inhibited the expression of inflammatory genes (i.e. IL-6 and MCP-1) in WAT explants as well as in adipocytes challenged with LPS. PGE2 anti-inflammatory actions were confirmed by microarray analysis of human pre-adipocytes incubated with this prostanoid. Moreover, PGE2 induced expression of brown markers (UCP1 and PRDM16) in WAT and adipocytes, but not in pre-adipocytes, suggesting that PGE2 might induce the trans-differentiation of adipocytes towards beige/brite cells. Finally, PGE2 inhibited isoproterenol-induced adipocyte lipolysis. Taken together, these findings identify PGE2 as a regulator of the complex network of interactions driving uncontrolled inflammation and fibrosis and impaired adaptive thermogenesis and lipolysis in human obese visceral WAT.
authors.affiliation: Department of Biochemistry and Molecular Genetics, Hospital Clínic-IDIBAPS, Barcelona, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: García-Alonso
authors.affiliation: Department of Biochemistry and Molecular Genetics, Hospital Clínic-IDIBAPS, Barcelona, Spain.|CIBERehd, Hospital Clínic-IDIBAPS, Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Titos
authors.affiliation: Department of Biochemistry and Molecular Genetics, Hospital Clínic-IDIBAPS, Barcelona, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Alcaraz-Quiles
authors.affiliation: Department of Biochemistry and Molecular Genetics, Hospital Clínic-IDIBAPS, Barcelona, Spain.
authors.forename: Bibiana
authors.initials: B
authors.lastname: Rius
authors.affiliation: Department of Biochemistry and Molecular Genetics, Hospital Clínic-IDIBAPS, Barcelona, Spain.
authors.forename: Aritz
authors.initials: A
authors.lastname: Lopategi
authors.affiliation: Department of Biochemistry and Molecular Genetics, Hospital Clínic-IDIBAPS, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: López-Vicario
authors.affiliation: Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Per-Johan
authors.initials: PJ
authors.lastname: Jakobsson
authors.affiliation: Department of Gastrointestinal Surgery, Hospital Clínic-IDIBAPS, Barcelona, Spain.
authors.forename: Salvadora
authors.initials: S
authors.lastname: Delgado
authors.affiliation: CIBERehd, Hospital Clínic-IDIBAPS, Barcelona, Spain.
authors.forename: Juanjo
authors.initials: J
authors.lastname: Lozano
authors.affiliation: Department of Biochemistry and Molecular Genetics, Hospital Clínic-IDIBAPS, Barcelona, Spain.|CIBERehd, Hospital Clínic-IDIBAPS, Barcelona, Spain.|Department of Biomedicine, University of Barcelona, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Clària
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D050156:Adipogenesis / Q000502:physiology; D052436:Adipose Tissue, White / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D008066:Lipolysis / Q000502:physiology*; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D022722:Thermogenesis / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D016212:Transforming Growth Factor beta; D051546:Cyclooxygenase 2; D015232:Dinoprostone