A translational study of miR-146a and miR-21 in glucocorticoid-associated lipodystrophy

• Grant number: 21/11174-6
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: January 01, 2022
• End date: June 30, 2022
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Alice Cristina Rodrigues
• Grantee: Anaysa Paola Bolin
• Supervisor: Yu-Hua Tseng
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Harvard University, Boston, United States
• Associated to the scholarship: 18/07241-7 - microRNAs participation in adipose tissue plasticity induced by iatrogenic chronic hypercortisolism, BP.PD

Abstract

Glucocorticoids excess in brown adipose tissue (BAT) has been proposed as an important negative modulator of thermogenesis through the mitochondrial uncoupling protein 1 (UCP1) inhibited expression. In addition to this factor, clinically, in humans, exposure to glucocorticoids excess with consequent disruption of the circadian rhythm of the hypothalamic-pituitary-adrenal axis is responsible for the redistribution of body fat and signs of metabolic syndrome in these patients. microRNAs (miRNAs, miR) are regulators of several biological processes that directly affect adipose tissue function and communication between metabolic organs. Our data demonstrate that glucocorticoid excess in rats induces a white cell phenotype in BAT with inhibition of thermogenic pathways and controls the expression of miRNAs such as miR-146a-5p and 21-5p. Furthermore, the data indicate that the expression of miR-146a-5p may be related to impaired functional brown cell adipogenesis and the high levels of miR-21-5p found in the tissue are derived from another cell or organ and demonstrate its communication with mediator cells. Genetic manipulations of adipose cells with the aim of modulating functional white adipocytes for activation of UCP1 protein expression has been shown to be effective in promoting beneficial effects in metabolic disorders. For this purpose, white human cells with a brown phenotype (human brown-like (HUMBLE) cells) were developed using Crisp-CAS9 technology. It is noteworthy to address the use of HUMBLE adipocytes in the treatment of metabolic disorders induced by hypercortisolism. Through this proposal, we propose to investigate whether miRs-146a and 21 are involved in lipodystrophy associated with glucocorticoids in immortalized human cells and whether the restoration to healthy levels found in BAT of control animals can reverse some of the effects of glucocorticoid on this tissue and, consequently, in metabolic complications. We intend to do this through a combination of functional and proteomic analysis, which will allow us to identify the role of these miRs in this context. In addition to characterizing the effect of serum from glucocorticoid-treated rats, we propose to investigate whether co-culture of HUMBLE cells with glucocorticoid-treated brown cells can reverse the white fat phenotype previously observed in these cells. This paper aims to clarify the possible use of HUMBLE adipocytes in the treatment of metabolic disorders induced by hypercortisolism, as long-term glucocorticoid therapy is often required for several chronic diseases. (AU)