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- Sarsenbayeva, Assel, et al.
(författare)
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Role of glucocorticoids in adipose tissue fibrosis and interplay between macrophages and adipose cells
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background and aimsExcessive endogenous production and administration of glucocorticoids leads to adipose tissue fibrosis as well as metabolic complications. Alternatively activated M2 macrophages are known to interfere with adipocyte differentiation and to promote phenotypic switch of preadipocytes into pro-fibrotic myofibroblasts. Glucocorticoids are known to promote M2 phenotype in macrophages. Therefore, the aim of this study was to investigate whether the effects of synthetic glucocorticoid dexamethasone on adipose tissue fibrosis are mediated through on macrophages to adipocyte communication. MethodsTranscriptomics analysis was performed on human adipose tissue treated without and with dexamethasone. We tested the effects of dexamethasone on differentiation of human SGBS adipocyte cells in the absence or presence of macrophages derived from THP-1 monocytic cell line plated on inserts. The differentiation rate was assessed by measuring cell lipid accumulation, expression of markers of adipogenesis PPARG and CEBPA. Acquisition of myofibroblast phenotype by preadipocytes was assessed by measuring the expression of myofibroblast marker α-smooth muscle actin. The pro-fibrotic activity of these cells was measured by the expression of collagen VI.ResultsOur transcriptomics data demonstrated that dexamethasone is able to directly double the expression of pro-fibrotic genes, such as CTGF, COL6A3, FN1, in adipose tissue, compared to control (p<0.05). Expression of CD163, a marker of M2 macrophages, positively correlated with the components of extracellular matrix COL6A3 and FN1 (p<0.01), and with the pro-fibrotic genes CTGF and AXL (p<0.01) in human adipose tissue. In addition, dexamethasone induced the expression of CD163 and MRC1 in THP-1 macrophages (p<0.05), suggesting that dexamethasone drives M2 phenotype in macrophages. We observed that dexamethasone inhibited adipogenesis by ~30% (p<0.01). Macrophages almost completely abolished differentiation of adipocytes by ~90% (p<0.01). Additionally, macrophages induced 2-3 fold increase in the expression of ACTA2 gene and protein in adipocytes (p<0.01). Dexamethasone alone did not affect ACTA2 in adipocytes,but in the presence of macrophages, increased ACTA2, when compared to macrophages alone (p<0.05). A similar nominal increase was observed in COL6A3. ConclusionOur data show that dexamethasone has a direct pro-fibrotic effect on adipose tissue and promotes M2 phenotype in macrophages. Furthermore, dexamethasone potentiated macrophage-induced phenotype switch of adipocytes to myofibroblasts, which suggests that its effect on adipose tissue fibrosis is mediated though macrophage-adipocyte communication.
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| 2. |
- Vranic, Milica, et al.
(författare)
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Effects of the second-generation antipsychotic drugs aripiprazole and olanzapine on human adipocyte differentiation
- 2023
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier. - 0303-7207 .- 1872-8057. ; 561
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Tidskriftsartikel (refereegranskat)abstract
- Second-generation antipsychotics (SGAs), used as the cornerstone treatment for schizophrenia and other mental disorders, can cause adverse metabolic effects (e.g. obesity and type 2 diabetes). We investigated the effects of SGAs on adipocyte differentiation and metabolism. The presence of therapeutic concentrations of aripiprazole (ARI) or its active metabolite dehydroaripiprazole (DARI) during human adipocyte differentiation impaired adipocyte glucose uptake while the expression of gene markers of fatty acid oxidation were increased. Additionally, the use of a supra-therapeutic concentration of ARI inhibited adipocyte differentiation. Furthermore, olanzapine (OLA), a highly obesogenic SGA, directly increased leptin gene expression but did not affect adipocyte differentiation and metabolism. These molecular insights are novel, and suggest that ARI, but not OLA, may directly act via alterations in adipocyte differentiation and potentially by causing a switch from glucose to lipid utilization in human adipocytes. Additionally, SGAs may effect crosstalk with other organs, such as the brain, to exert their adverse metabolic effects.
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