title: Anti-Inflammatory Effects of Rosiglitazone in Obesity-Impaired Wound Healing Depend on Adipocyte Differentiation.
abstract: Combined diabetes-obesity syndromes severely impair regeneration of acute skin wounds in mouse models. This study assessed the contribution of subcutaneous adipose tissue to exacerbated wound inflammatory conditions. Genetically obese (ob/ob) mice showed an increased expression of positive transcriptional effectors of adipocyte differentiation such as Krüppel-like factor (KLF)-5 and peroxisome proliferator-activated receptor (PPAR)-γ and an associated expression of leptin and fatty acid-binding protein (FABP)-4, but also CXCL2 in isolated subcutaneous fat. This observation in obese mice is in keeping with differentially elevated levels of KLF-5, PPAR-γ, leptin, FABP-4 and CXCL2 in in vitro-differentiated 3T3-L1 adipocytes. Notably, CXCL2 expression restrictively appeared upon cytokine (IL-1β/TNF-α) stimulation only in mature, but not immature 3T3-L1 adipocytes. Of importance, the critical regulator of adipocyte maturation, PPAR-γ, was merely expressed in the final phase of in-vitro induced adipocyte differentiation from 3T3-L1 pre-adipocytes. Consistently, the PPAR-γ agonist rosiglitazone suppressed cytokine-induced CXCL2 release from mature adipocytes, but not from early 3T3-L1 adipocyte stages. The inhibitory effect of PPAR-γ activation on CXCL2 release appeared to be a general anti-inflammatory effect in mature adipocytes, as cytokine-induced cyclooxygenase (Cox)-2 was simultaneously repressed by rosiglitazone. In accordance with these findings, oral administration of rosiglitazone to wounded obese mice significantly changed subcutaneous adipocyte morphology, reduced wound CXCL2 and Cox-2 expression and improved tissue regeneration. Thus, our data suggest that PPAR-γ might provide a target to suppress inflammatory signals from mature adipocytes, which add to the prolonged wound inflammation observed in diabetes-obesity conditions.
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, Frankfurt am Main, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Siebert
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, Frankfurt am Main, Germany.
authors.forename: Itamar
authors.initials: I
authors.lastname: Goren
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, Frankfurt am Main, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, Frankfurt am Main, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Frank
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D054426:Chemokine CXCL2 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D005260:Female; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D047495:PPAR gamma / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; C118391:Klf5 protein, mouse; D051741:Kruppel-Like Transcription Factors; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2