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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. [ABSTRACT FROM AUTHOR]