Abstract
BackgroundAdipocyte accumulation is a predominant feature of age-related thymic involution, but the mechanisms responsible for thymic adipogenesis remain to be elucidated. The aim of this study was to identify key regulators in thymic adipogenesis. We used rosiglitazone, a potent peroxisome proliferator-activated receptor γ (PPARγ) agonist, to induce adipogenic differentiation of OP9-DL1 cells, and investigated the differentially expressed proteins during adipogenic differentiation by using label-free quantitative proteomics. Furthermore, the effects of transforming growth factor β1 (TGF-β1) on rosiglitazone-induced adipogenic differentiation of OP9-DL1 cells as well as the underlying mechanisms were also investigated.ResultsProteomic analysis identified 139 proteins differed significantly in rosiglitazone-treated cells compared with dimethyl sulphoxide (DMSO)-treated cells. Rosiglitazone-induced adipogenic differentiation was inhibited by TGF-β1 treatment in OP9-DL1 cells and primary thymic stromal cells. Real-time PCR analysis showed significant increases in PPARγ and fatty acid binding protein 4 mRNA levels in rosiglitazone-treated cells, which were inhibited by TGF-β1 treatment. TGF-β1 down-regulated PPARγ expression at both mRNA and protein levels in OP9-DL1 cells. Chromatin immunoprecipitation analysis demonstrated that TGF-β1 enhanced the binding of Smad2/3 and histone deacetylase 1, but reduced the binding of H3K14ac to the promoter of PPARγ gene. TGF-β1 partially reversed the inhibitory effects of rosiglitazone on the expression of Axin2 and β-catenin protein levels. TGF-β1 inhibited rosiglitazone-induced adipogenic transformation in OP9-DL1 cells by down-regulation of PPARγ and activation of the canonical Wnt/β-catenin signaling pathway.ConclusionTaken together, activation of TGF-β pathway may serve as a useful strategy to prevent thymic adiposity in age-related thymic involution.
Highlights
The thymus represents a specialized primary lymphoid organ that provides the initial site and appropriate microenvironments to facilitate the differentiation, development and maturation of T cells [3]
We evaluated whether transforming growth factor β1 (TGF-β1) inhibits rosiglitazone-induced adipogenic differentiation in OP9-DL1 cells and primary Thymic stromal cells (TSCs) and, if so, whether the inhibitory effects of TGF-β1 are associated with down-regulation of peroxisome proliferator-activated receptor γ (PPARγ) and activation of the canonical Wnt/β-catenin signaling pathway in OP9-DL1 cells
Identification of differentially expressed proteins during adipogenic transformation in OP9‐DL1 cells To investigate the mechanisms responsible for thymic adiposity, proteomic analysis was conducted on rosiglitazone- and dimethyl sulphoxide (DMSO)-treated OP9-DL1 cells
Summary
The thymus represents a specialized primary lymphoid organ that provides the initial site and appropriate microenvironments to facilitate the differentiation, development and maturation of T cells [3]. After reaching its maximum weight in puberty, the thymus begins to atrophy slowly and steadily with advancing age [1] This physiological process, known as age-related involution, is characterized by a decline in thymic weight and size, disruption of thymic architecture, loss of thymic epithelial cells, and adipocyte accumulation, thereby resulting in reduced naïve T cell output and increased susceptibility to infection, autoimmune disease, and cancer in the elderly [13]. Adipocyte accumulation is a predominant feature of age-related thymic involution and has a detrimental effect on thymic microenvironments [8, 35]. Adipocyte accumulation is a predominant feature of age-related thymic involution, but the mechanisms responsible for thymic adipogenesis remain to be elucidated. The effects of transforming growth factor β1 (TGF-β1) on rosiglitazone-induced adipogenic differentiation of OP9-DL1 cells as well as the underlying mechanisms were investigated
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