Department of Experimental Medical Science, Lund University, Sweden.
Department of Experimental Medical Science, Lund University, Sweden.
Life Sci. 2022 Jun 15;299:120537. doi: 10.1016/j.lfs.2022.120537. Epub 2022 Apr 7.
To accommodate surplus energy, adipose tissue expands by increasing both adipose cell size (hypertrophy) and cell number (hyperplasia). Enlarged, hypertrophic adipocytes are known to have reduced insulin response and impaired glucose transport, which negatively influence whole-body glucose homeostasis. Rosiglitazone is a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, known to stimulate hyperplasia and to efficiently improve insulin sensitivity. Still, a limited amount of research has investigated the effects of rosiglitazone in mature, hypertrophic adipocytes. Therefore, the objective of this study was to examine rosiglitazone's effect on insulin-stimulated glucose uptake in hypertrophic adipocytes.
C57BL/6J male mice were subjected to 2 weeks of high-fat diet (HFD) followed by 1 week of HFD combined with daily administration of rosiglitazone (10 mg/kg). Adipose cell-size distribution and gene expression were analysed in intact adipose tissue, and glucose uptake, insulin response, and protein expression were examined using primary adipocytes isolated from epididymal and inguinal adipose tissue.
HFD-feeding induced an accumulation of hypertrophic adipocytes, which was not affected by rosiglitazone-treatment. Still, rosiglitazone efficiently improved insulin-stimulated glucose transport without restoring insulin signaling or GLUT4 expression in similar-sized adipocytes. This improvement occurred concurrently with extracellular matrix remodelling and restored intracellular levels of targets involved in actin turnover.
These results demonstrate that rosiglitazone improves glucose transport in hypertrophic adipocytes, and highlights the importance of the cytoskeleton and extracellular matrix as potential therapeutic targets.
为了容纳多余的能量，脂肪组织通过增加脂肪细胞大小（肥大）和细胞数量（增生）来扩张。已知增大的肥大脂肪细胞对胰岛素的反应降低，葡萄糖转运受损，这对全身葡萄糖稳态产生负面影响。罗格列酮是过氧化物酶体增殖物激活受体γ（PPARγ）激动剂，已知可刺激增生并有效改善胰岛素敏感性。尽管如此，关于罗格列酮在成熟肥大脂肪细胞中的作用的研究有限。因此，本研究的目的是研究罗格列酮对肥大脂肪细胞中胰岛素刺激的葡萄糖摄取的影响。
C57BL/6J 雄性小鼠接受 2 周高脂肪饮食（HFD），然后再接受 1 周 HFD 并每天给予罗格列酮（10mg/kg）。分析完整脂肪组织中的脂肪细胞大小分布和基因表达，并使用从附睾和腹股沟脂肪组织分离的原代脂肪细胞检查葡萄糖摄取、胰岛素反应和蛋白质表达。
HFD 喂养导致肥大脂肪细胞的积累，而罗格列酮处理对此没有影响。然而，罗格列酮有效地改善了胰岛素刺激的葡萄糖转运，而没有恢复相似大小的脂肪细胞中的胰岛素信号或 GLUT4 表达。这种改善伴随着细胞外基质重塑和恢复参与肌动蛋白周转的细胞内靶标水平。
这些结果表明，罗格列酮可改善肥大脂肪细胞中的葡萄糖转运，并强调细胞骨架和细胞外基质作为潜在治疗靶点的重要性。
