microRNAs participation in adipose tissue plasticity induced by iatrogenic chronic hypercortisolism

• Grant number: 18/07241-7
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: June 01, 2018
• End date: April 30, 2023
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Alice Cristina Rodrigues
• Grantee: Anaysa Paola Bolin
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 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, AP.TEM
• Associated scholarship(s): 21/11174-6 - A translational study of miR-146a and miR-21 in glucocorticoid-associated lipodystrophy, BE.EP.PD

Abstract

Cushing's syndrome (endogenous or iatrogenic) includes a group of diseases that are characterized by excessive exposure to glucocorticoids, with consequent circadian rhythm breakdown of the hypothalamic-pituitary-adrenal axis. From the clinical point of view, in humans, the panorama is the body fat redistribution with increased central adiposity and reduction in limbs. At the same time, there is a picture of the metabolic syndrome with its classic components: insulin resistance (leading to type 2 diabetes mellitus), dyslipidemia, increased susceptibility to systemic arterial hypertension, and other signs and symptoms, including muscular atrophy, osteopenia, abdominal striae, and exacerbated protein catabolism. microRNAs (miRNAs; miRs) are small RNAs, 19-22 nucleotides, not coding. They are located in intergenic or intron regions of other genes and are generally involved in the post-transcriptional regulation of gene expression acting by translational repression, promoting the degradation of mRNA by partial pairing of bases in the 3'UTR region of target mRNAs. Recently, microRNAs participation in the glucocorticoids effect on the adipose tissue functionality has been shown. Glucocorticoids via glucocorticoid receptor increase the expression of miR-27b by a direct mechanism (i.e., through responsive elements to glucocorticoids in the miR-27b promoter), decreasing the browning effect of white adipose tissue through Prdm16. Blockade of miR-27b by anti-miR-27b-containing lentivirus injection reduced visceral and subcutaneous fat deposits, increased heat production, oxygen uptake, and CO2 production. In addition, inhibition of miR-27b has improved glucose intolerance induced by dexamethasone. These findings are promising and raise the possibility that miR-27b is a therapeutic target in the metabolic dysfunction prevention or treatment caused by glucocorticoids. On the other hand, several other microRNAS were regulated by dexamethasone treatment and were even differentially expressed between visceral and subcutaneous fat that were not investigated in the study mentioned above and may play a role in the accumulation of visceral adipose tissue in Cushing's syndrome. In addition, the microRNAs also participate in the anti-inflammatory action of glucocorticoids. Prednisolone-treated CD4 + T cells had increased miR-98, which inhibits several pro-inflammatory targets such as interleukins -13 and 3 and tumor necrosis factor receptors, again evidencing the action of glucocorticoids through microRNAs. We consider the Cushing iatrogenic model approach to better understand the mechanisms involved in adipose tissue plasticity induced by glucocorticoids and also the participation of microRNAs in this process. A better understanding of how glucocorticoids act is important to understand their role in the induction of Cushing phenotype and how glucocorticoids act to promote visceral fat accumulation.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

RODRIGUES, ALICE C.; SPAGNOL, ALEXANDRE R.; FRIAS, FLAVIA DE TOLEDO; DE MENDONCA, MARIANA; ARAUJO, HYGOR N.; GUIMARAES, DIMITRIUS; SILVA, WILLIAM J.; BOLIN, ANAYSA PAOLA; MURATA, GILSON MASAHIRO; SILVEIRA, LEONARDO. ntramuscular Injection of miR-1 Reduces Insulin Resistance in Obese Mic. FRONTIERS IN PHYSIOLOGY, v. 12, JUL 6 2021. (20/08049-2, 11/05876-6, 17/19513-9, 18/07087-8, 18/07241-7, 15/24789-8)