Glucocorticoid modulates oxidative and thermogenic function of rat brown adipose tissue and human brown adipocytes.

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.

Sex-specific regulation of miR-22 and ERα in white adipose tissue of obese dam's female offspring impairs the early postnatal development of functional beige adipocytes in mice.

During inguinal adipose tissue (iWAT) ontogenesis, beige adipocytes spontaneously appear between postnatal 10 (P10) and P20 and their ablation impairs iWAT browning capacity in adulthood. Since maternal obesity has deleterious effects on offspring iWAT function, we aimed to investigate its effect in spontaneous iWAT browning in offspring. Female C57BL/6 J mice were fed a control or obesogenic diet six weeks before mating. Male and female offspring were euthanized at P10 and P20 or weaned at P21 and fed chow diet until P60. At P50, mice were treated with saline or CL316,243, a ß3-adrenoceptor agonist, for ten days. Maternal obesity induced insulin resistance at P60, and CL316,243 treatment effectively restored insulin sensitivity in male but not female offspring. This discrepancy occurred due to female offspring severe browning impairment. During development, the spontaneous iWAT browning and sympathetic nerve branching at P20 were severely impaired in female obese dam's offspring but occurred normally in males. Additionally, maternal obesity increased miR-22 expression in the iWAT of male and female offspring during development. ERα, a target and regulator of miR-22, was concomitantly upregulated in the male's iWAT. Next, we evaluated miR-22 knockout (KO) offspring at P10 and P20. The miR-22 deficiency does not affect spontaneous iWAT browning in females and, surprisingly, anticipates iWAT browning in males. In conclusion, maternal obesity impairs functional iWAT development in the offspring in a sex-specific way that seems to be driven by miR-22 levels and ERα signaling. This impacts adult browning capacity and glucose homeostasis, especially in female offspring.

Long-term glucocorticoid infusion impairs epididymal adipocyte metabolism and maturation and affects miR-150-5p actions.

The most common form of hypercortisolism is iatrogenic Cushing's syndrome. Lipodystrophy and metabolic disorders can result from the use of exogenous glucocorticoids (GC). Adipocytes play an important role in the production of circulating exosomal microRNAs, and knockdown of Dicer promotes lipodystrophy. The aim of this study is to investigate the effect of GCs on epididymal fat and to assess their influence on circulating microRNAs associated with fat turnover. The data indicate that despite the reduction in adipocyte volume due to increased lipolysis and apoptosis, there is no difference in tissue mass, suggesting that epididymal fat pad, related to animal size, is not affected by GC treatment. Although high concentrations of GC have no direct effect on epididymal microRNA-150-5p expression, GC can induce epididymal adipocyte uptake of microRNA-150-5p, which regulates transcription factor Ppar gamma during adipocyte maturation. In addition, GC treatment increased lipolysis and decreased glucose-derived lipid and glycerol incorporation. In conclusion, the similar control and GC epididymal fat mass results from increased dense fibrogenic tissue and decreased adipocyte volume induced by the lipolytic effect of GC. These findings demonstrate the complexity of epididymal fat. They also highlight how this disease alters fat distribution. This study is the first in a series published by our laboratory showing the detailed mechanism of adipocyte turnover in this disease.