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Molecular mechanisms involved in the metabolic inflexibility of rats submitted to metabolic programming induced by prenatal excess of glucocorticoids

Grant number: 19/03196-0
Support type:Regular Research Grants
Duration: March 01, 2020 - February 28, 2022
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Silvana Auxiliadora Bordin da Silva
Grantee:Silvana Auxiliadora Bordin da Silva
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Dynamic metabolic regulation by the liver is essential for the maintenance of energy metabolism and the organism survival. During fasting, the liver produces glucose to supply the metabolic demand of the organism. Recently, we have demonstrated that rats born to dexamethasone-treated mothers do not increase hepatic glucose production adequately when subjected to prolonged fasting, which indicates impairment in the metabolic flexibility. In an attempt to elucidate the genesis of this phenomenon, we have investigated the expression of two key proteins involved in the regulation of the energy metabolism: (1) FGF21, the hepatic hormone induced by fasting that regulates fuel catabolism and production; (2) PGC-1±, a key transcriptional coactivator of energy metabolism that is regulated by FGF21. Our results showed that both were downregulated by fetal dexamethasone-treatment; however, the patterns observed in our experiments do not match with the reported data. Otherwise, the long-lasting effects indicate the involvement of epigenetic mechanisms, and that it would depend on a complex interaction between the latter and the direct effects of glucocorticoids. Thus, in this project we will evaluate the time-course and the fuel modulation of the expression of FGF21, PGC-1± its potential regulators (DNA methylation, miRNA expression) and effectors (PPAR±, FoxO, GR) in the liver of rats born to dexamethasone-treated mothers. For this, rats born to dexamethasone-treated mothers during the 3rd period of gestation will be euthanized at the 1st, 8th, and 21th day of lactation, and at the 120th of life. In the latter period, control and dexamethasone-treated groups will be divided in 3 subgroups: rats submitted to physiological fasting of 12h (CTL), prolonged fasting of 60h (JJ60) and prolonged fasting followed by 4h-refeeding (JJ60+RF). The expression of FGF21, PGC-1±, FoxO1, GR, and PPAR± will be analyzed by qPCR and Western blot. The potential mechanisms of regulation of PGC-1± will be verified by the analysis of gene methylation and the expression of miR-29 family, previously described as regulators of PGC-1±. The significance of altered PGC-1± will be investigated by the quantification of mitochondrial DNA and the activity of metabolic enzymes. We expected to identify potential targets to further and deeper investigation, using pharmacological and/or molecular tools. (AU)