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.

Adipose-Derived Stromal Cells Attenuate Adipose Inflammation in Obesity through Adipocyte Browning and Polarization of M2 Macrophages

“…This finding was consistent with the conclusion of Li et al [28]. Additionally, Siebert et al [29] demonstrated that rosiglitazone had anti-inflammatory effects through its effect on PPAR- γ protein in adipocytes. Similarly, our results indicated that obese mice which received rosiglitazone treatment had significantly decreased levels of ITGAM and NF- κ B protein expression associated with inflammatory response and had decreased levels of polarized M2 macrophages, which ultimately suppressed the production of proinflammatory cytokines TNF- α , IL-6, and IL-1 β and promoted the secretion of anti-inflammatory cytokine IL-10.…”

Scrutinizing Mechanisms of the ‘Obesity Paradox in Sepsis’: Obesity Is Accompanied by Diminished Formation of Neutrophil Extracellular Traps (NETs) Due to Restricted Neutrophil–Platelet Interactions

“…In mice CXCL1 (KC) and CXCL2 (MIP-2), acting via CXCR2, regulate neutrophil chemotaxis and their levels are enhanced in obese individuals [ 45 , 46 ]. We evaluated the dependence of neutrophil infiltration into liver sinusoids on CXCR2 by pretreating obese and lean mice with its antagonist.…”

Preconditioning Human Adipose-Derived Stromal Cells on Decellularized Adipose Tissue Scaffolds Within a Perfusion Bioreactor Modulates Cell Phenotype and Promotes a Pro-regenerative Host Response

“…Chemokine C-X-C motif 10 (CXCL-10) was selected as a marker associated with inflammation in adipose tissue (Kochumon et al, 2020), as well as macrophage recruitment in other tissues (Petrovic-Djergovic et al, 2015). Finally, C-X-C motif ligand 2 (CXCL-2) was chosen as a pro-inflammatory chemokine that has been shown to be upregulated during adipogenic differentiation (Kusuyama et al, 2016;Siebert et al, 2016), and interleukin-6 (IL-6) was included as an additional pro-inflammatory adipokine that can modulate both lipid metabolism and macrophage polarization within adipose tissue (Trujillo et al, 2004;Braune et al, 2017). For this assay, three replicate scaffolds from each group (n = 3) were analyzed per ASC donor, and a total of five trials were performed with different ASC donors (N = 5).…”