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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

Grant number: 16/25129-4
Support type:Research Projects - Thematic Grants
Duration: November 01, 2017 - October 31, 2022
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Fabio Bessa Lima
Grantee:Fabio Bessa Lima
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo, SP, Brazil
Co-Principal Investigators:Alice Cristina Rodrigues
Assoc. researchers:Marilia Cerqueira Leite Seelaender ; Rogério Antônio Laurato Sertié ; Sheila Collins


The Cushing's Syndrome encompasses a set of malaises characterized by an excessive and chronic (endogenous or iatrogenic) exposition to glucocorticoids that leads to a disruption of the circadian rhythm the hypothalamic-hypophyseal-adrenal axis. Clinically, in humans, the picture is manifested by a body fat redistribution with increase in the central (truncal) part of the body and reduction in the limbs. In parallel, patients develop signs of metabolic syndrome such as: insulin resistance (that can lead to Type 2 Diabetes Mellitus), Dyslipidemia, higher susceptibility to systemic Arterial Hypertension, and other signals and symptoms, like Abdominal Stria, Muscular Atrophy, Osteopenia, and exacerbated protein catabolism. The reproduction of this syndrome in rodents brings some technical difficulties, particularly relating to its clinical characterization, which has some differences of that seen in humans. Anyway, in recent study of our group, we tried a model of iatrogenic glucocorticoid prolonged and constant infusion (throughout a 4-week period) by means of an osmotic minipump in rats and we obtained a metabolic picture in which there was a more centripetal distribution of fat together with insulin resistance, glucose intolerance, and Bilateral Adrenal Hypotrophy characteristic of hypothalamic-pituitary-adrenal axis disruption. Using this model, we aim to assess the mechanisms that govern with the pattern of adipose tissue distribution in the body and how glucocorticoids interfere and modify it. More specifically, our objective is to investigate how glucocorticoids alter the profile of adipocyte biological responses (including lipolytic and lipogenic capacities and glyceroneogenesis), the adipose cell turnover (adipogenesis and apoptosis) and the distribution and function of white, brown and beige fats (through the evaluation of the thermogenic responsiveness and mitochondrial biogenesis) in distinct body fat regions (inguinal and interescapular subcutaneous, and epididymal, mesenteric and retroperitoneal visceral fats). For all these analyses, in vivo and in vitro approaches will be employed as well as molecular studies (protein [western blotting] and mRNAs [RT-PCT] and microRNAs [miR] expression). Details about all the aspects above mentioned are included in the body of the project. We consider that this model of iatrogenic induction of the Cushing's syndrome is an interesting and ideal approach to understand how the changes in the adipose tissue plasticity dynamics take place and which underlying mechanisms influence on its regulation. We believe that the knowledge that will emerge from this study can contribute to improve the strategies to deal with obesity and lipodystrophy. (AU)