Abstract：
Chronic and excessive glucocorticoid (GC) exposure can cause Cushing\'s syndrome, resulting in fat accumulation in selected body areas. Particularly in the brown adipose tissue (BAT), GC acts negatively, resulting in whitening of the tissue. We hypothesized that dysregulation of microRNAs by GC could be an additional mechanism to explain its negative actions in BAT. Male Wistar rats were divided into two groups: (1) Control sham and (2) GC group that was administered dexamethasone 6.25 mg/200 μL via osmotic pump implantation over 28 days. After this period, the animals were euthanized and BAT tissue was properly stored. Human fat cells treated with dexamethasone were used to translate the experimental results found in animals to human biology. GC-treated rat BAT presented with large lipid droplets, severely impaired thermogenic activation, and reduced glucose uptake measured by 18F-FDG PET/CT. GC exposure induced a reduction in the mitochondrial OXPHOS system and oxygen consumption. MicroRNA profiling of BAT revealed five top-regulated microRNAs and among them miR-21-5p was the most significantly upregulated in GC-treated rats compared to the control group. Although upregulation of miR-21-5p in the tissue, differentiated primary brown adipocytes from GC-treated rats had decreased miR-21-5p levels compared to the control group. To translate these results to the clinic, human brown adipocytes were treated with dexamethasone and miR-21-5p inhibitor. In human brown cells, inhibition of miR-21-5p increased brown adipocyte differentiation and prevented GC-induced glucose uptake, resulting in a lower glycolysis rate. In conclusion, high-dose GC therapy significantly impacts brown adipose tissue function, with a notable association between glucose uptake and miR-21-5p.
摘要：
慢性和过度糖皮质激素（GC）暴露可导致库欣综合征，导致脂肪堆积在选定的身体区域。特别是在棕色脂肪组织（BAT）中，GC行为消极，导致组织变白。我们假设GC对microRNA的失调可能是解释其在BAT中的负面作用的另一种机制。雄性Wistar大鼠分为两组：（1）对照组和（2）GC组，通过渗透泵植入28天给予地塞米松6.25mg/200μL。在这段时间之后,将动物安乐死并适当储存BAT组织。用地塞米松处理的人脂肪细胞用于将在动物中发现的实验结果转化为人类生物学。GC处理的大鼠BAT呈现大的脂滴，严重受损的产热激活，18F-FDGPET/CT测得的葡萄糖摄取减少。GC暴露诱导线粒体OXPHOS系统和氧消耗的减少。BAT的MicroRNA分析揭示了五种最高调节的microRNA，其中miR-21-5p在GC处理的大鼠中与对照组相比最显著上调。尽管miR-21-5p在组织中上调，与对照组相比,来自GC处理的大鼠的分化的原代棕色脂肪细胞具有降低的miR-21-5p水平.为了将这些结果转化为诊所，用地塞米松和miR-21-5p抑制剂治疗人棕色脂肪细胞.在人类棕色细胞中，抑制miR-21-5p可增加棕色脂肪细胞分化并阻止GC诱导的葡萄糖摄取，导致较低的糖酵解率。总之,大剂量GC治疗显著影响棕色脂肪组织功能，葡萄糖摄取与miR-21-5p之间存在显著关联。
