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P38alpha MAPK role in the beta-adrenergic pathways, browning and whitening of adipose tissue in an experimental model of chronic iatrogenic hypercortisolism

Grant number: 19/04936-7
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): June 01, 2019
Effective date (End): May 31, 2020
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Fabio Bessa Lima
Grantee:Flaviane de Fatima Silva
Supervisor abroad: Sheila Ann Collins
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Local de pesquisa : Vanderbilt University (VU), United States  
Associated to the scholarship: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, BP.DR

Abstract

Obesity/adipose redistribution is one of the characteristics of hypercortisolism/Cushing's syndrome, reproduced in our experimental model of hypercortisolism in rats. Our goal is to understand how glucocorticoid excess affect browning and whitening process in various fat deposits and whether these effects correlate with the fat redistribution in this pathological state. Partial results indicate the occurrence whitening of interscapular BAT, as there is an important morphological alteration of the adipocytes, which acquire unilocular characteristics and have reduced oxidative capacity for both glucose and fatty acids, as well as a significant reduction of the citrate synthase activity and Ucp1 gene expression. In the inguinal subcutaneous fat, an increase in the oxidative capacity for both substrates was observed, accompanied by an increase in the citrate synthase activity and the Ucp1 gene expression, suggesting browning in this deposit. One of the main stimuli for the activation of beige and brown adipocytes is adrenergic activation, mainly by type 3 beta-receptor. Previous studies have shown that the increase in Ucp1 expression due to adrenergic activation is dependent on the p38± MAPK pathway. However, one of the routes by which glucocorticoids play their anti-inflammatory effect on different cell types is by inhibition of MAPKs. In view of this, the questions are: (1) "browning"/"whitening" is related to the inhibitory effect of glucocorticoids on MAPKs, especially on p38± MAPK? (2) Does MAPK inhibition alter beta-adrenergic activation of different tissues and consequently alters "browning"/"whitening"? Thus, the objective of this project is to evaluate the role of p38± MAPK in ²-adrenergic pathways and in the "browning"/"whitening" processes of different adipose deposits in an experimental model of chronic iatrogenic hypercortisolism.