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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)-? 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-?, leptin, FABP-4 and CXCL2 in in vitro-differentiated 3T3-L1 adipocytes. Notably, CXCL2 expression restrictively appeared upon cytokine (IL-1?/TNF-?) stimulation only in mature, but not immature 3T3-L1 adipocytes. Of importance, the critical regulator of adipocyte maturation, PPAR-?, was merely expressed in the final phase of in-vitro induced adipocyte differentiation from 3T3-L1 pre-adipocytes. Consistently, the PPAR-? agonist rosiglitazone suppressed cytokine-induced CXCL2 release from mature adipocytes, but not from early 3T3-L1 adipocyte stages. The inhibitory effect of PPAR-? 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-? might provide a target to suppress inflammatory signals from mature adipocytes, which add to the prolonged wound inflammation observed in diabetes-obesity conditions.

SUBMITTER: Siebert A

PROVIDER: S-EPMC5167406 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Anti-Inflammatory Effects of Rosiglitazone in Obesity-Impaired Wound Healing Depend on Adipocyte Differentiation.

Siebert Anna A Goren Itamar I Pfeilschifter Josef J Frank Stefan S

PloS one 20161219 12

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 ...[more]

PMID: 27992530

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Project description:BackgroundWound healing (WH) is a complex process involving several stages, such as hemostasis, inflammation, re-epithelialization, and remodeling. Many factors can impair WH, and different pharmacological approaches were studied to date, but the increase in antibiotic resistance, invasiveness, treatment duration, and high cost, have often hampered the resolution of the wound. In this study, we investigated the possible application of water-soluble carvacrol prodrugs (WSCPs) and hyaluronic acid (HA) and their formulations (WSCPs/HA) to improve WH and regulate the inflammatory response.Materials and methodsFirstly, the cytotoxicity of 0.1, 1 and 10 µg/mL of HA, WSCPs and WSCPs/HA formulations were evaluated on HaCaT cells and THP-1 cell lines. The ability of WSCPs/HA formulations to modulate wound repair was evaluated in an in vitro model of WH, using HaCaT cells at 6, 18, and 24 h. The expression of WH mediators, after wound closure was determined by qRT-PCR. Following, we polarized THP-1 cells in M1/M2-like macrophages and tested the anti-inflammatory properties of WSCPs/HA formulations. After, we tested the in vitro WH model for the effects of conditioned medium (CM) from M1/M2-like cells cultured in the presence of WSCPs/HA.ResultsResults showed that WSCPs/HA formulations were able to significantly raise the wound closure rate, compared to the single constituents, promoting a complete wound closure after 18 h for WSCP1/HA (10 µg/mL) and after 24 h for WSCP2/HA (10 µg/mL), modulating the MMPs, TGFβ, and COX-2 gene expression. The effects of CM derived from M1/M2 polarized cells cultured in the presence of WSCPs/HA determined WH regulation, with a better ability of the WSCP2/HA formulation to modulate the time-dependent expression of reparative and inflammatory mediators.ConclusionOur data underline the possible application of WSCPs/HA formulations as bioactive agents for the regulation of the wound repair process by the modulation of inflammatory and remodeling phases, affecting the activity of immune cells.

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Anti-Inflammatory Effects of Rosiglitazone in Obesity-Impaired Wound Healing Depend on Adipocyte Differentiation.

Publications

Anti-Inflammatory Effects of Rosiglitazone in Obesity-Impaired Wound Healing Depend on Adipocyte Differentiation.

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