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

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Bolin, Anaysa Paola ; Silva, Flaviane de Fatima ; Salgueiro, Rafael Barrera ; dos Santos, Bruna Araujo ; Komino, Ayumi Cristina Medeiros ; Andreotti, Sandra ; de Sousa, Erica ; de Castro, Erique ; Real, Caroline Cristiano ; Faria, Daniele de Paula ; Souza, Gerson Profeta ; Camara, Henrique ; Sorgi, Carlos Arterio ; Tseng, Yu-Hua ; Lima, Fabio Bessa ; Rodrigues, Alice Cristina

• Document type: Journal article
• Source: Journal of Cellular Physiology; v. 239, n. 9, p. 12-pg., 2024-08-01.

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 mu L 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 F-18-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. (AU)

• FAPESP's process: 18/15167-1 - Translational neuroimaging in intellectual disability: evaluation of molecular changes associated with aging in Down Syndrome
• Grantee: Daniele de Paula Faria
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 21/11174-6 - A translational study of miR-146a and miR-21 in glucocorticoid-associated lipodystrophy
• Grantee: Anaysa Paola Bolin
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 16/08202-0 - Evaluation of adipose tissue microRNA expression regulating neuro-adipose crosstalk in hyperlipidic diet induced obese mice offspring
• Grantee: Erica de Sousa
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 18/16856-5 - Study of alterations in lipolytic response and glyceroneogenesis in adipose territories of different anatomical locations induced by chronic iatrogenic hypercortisolism
• Grantee: Ayumi Cristina Medeiros Komino
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 22/01363-9 - The effect of glucocorticoid and/or insulin treatment in the exosomal miRNAs profile of different adipocytes
• Grantee: Rafael Barrera Salgueiro
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 16/25129-4 - Iatrogenic Chronic Hypercortisolism and its implications to the adipose tissue plasticity an analysis of the dynamics of adipose tissue distribution in an experimental model of Cushing's Syndrome
• Grantee: Fabio Bessa Lima
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/19669-4 - Alterations in adipogenesis and apoptosis in different adipose territories induced by the chronic iatrogenic hypercortisolism
• Grantee: Rafael Barrera Salgueiro
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/07241-7 - microRNAs participation in adipose tissue plasticity induced by iatrogenic chronic hypercortisolism
• Grantee: Anaysa Paola Bolin
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/11145-3 - Study of alterations in thermogenic capacity and regulation of browning / whitening in adipose territories of different anatomical locations induced by chronic iatrogenic hypercortisolism
• Grantee: Flaviane de Fatima Silva
• Support Opportunities: Scholarships in Brazil - Doctorate