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 Opportunities: Regular Research Grants
• Start date: March 01, 2020
• End date: 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
• Host 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)

Scientific publications

(8)

(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)

PEREIRA, GIZELA A.; SODRE, FRHANCIELLY S.; MURATA, GILSON M.; AMARAL, ANDRESSA G.; PAYOLLA, TANYARA B.; CAMPOS, CAROLINA V.; SATO, FABIO T.; ANHE, GABRIEL F.; BORDIN, SILVANA. Fructose Consumption by Adult Rats Exposed to Dexamethasone In Utero Changes the Phenotype of Intestinal Epithelial Cells and Exacerbates Intestinal Gluconeogenesis. NUTRIENTS, v. 12, n. 10, OCT 2020. (19/03196-0, 13/07607-8)

DE SOUZA, DAILSON NOGUEIRA; TEIXEIRA, CAIO JORDAO; VERONESI, VANESSA BARBOSA; MURATA, GILSON MASAHIRO; SANTOS-SILVA, JUNIA CAROLINA; HECHT, FERNANDA BALLERINI; VICENTE, JULIA MODESTO; BORDIN, SILVANA; ANHE, GABRIEL FORATO. Dexamethasone programs lower fatty acid absorption and reduced PPAR-gamma and fat/CD36 expression in the jejunum of the adult rat offspring. Life Sciences, v. 265, JAN 15 2021. (13/07607-8, 20/06397-3, 19/03196-0, 16/13138-9, 15/23285-6)

ANHE, GABRIEL FORATO; BORDIN, SILVANA. The adaptation of maternal energy metabolism to lactation and its underlying mechanisms. Molecular and Cellular Endocrinology, v. 553, p. 22-pg., 2022-06-11. (13/07607-8, 20/13940-5, 19/03196-0)

ASSALIN, HELOISA B.; GABRIEL DE ALMEIDA, KELLY CRISTIANE; GUADAGNINI, DIOZE; SANTOS, ANDREY; TEIXEIRA, CAIO J.; BORDIN, SILVANA; ROCHA, GUILHERME Z.; SAAD, MARIO J. A.. Proton Pump Inhibitor Pantoprazole Modulates Intestinal Microbiota and Induces TLR4 Signaling and Fibrosis in Mouse Liver. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 23, n. 22, p. 18-pg., 2022-11-01. (19/03196-0, 14/50907-5, 20/06397-3)

VICENTE, JULIA MODESTO; LESCANO, CAROLINE HONAISER; BORDIN, SILVANA; MONICA, FABIOLA ZAKIA; GOBBI, GABRIELLA; ANHE, GABRIEL FORATO. Agomelatine inhibits platelet aggregation through melatonin receptor-dependent and independent mechanisms. Life Sciences, v. 328, p. 14-pg., 2023-09-01. (19/03196-0, 13/07607-8, 19/19488-0, 20/13940-5)

VERONESI, VANESSA BARBOSA; PIOLI, MARIANA RODRIGUES; DE SOUZA, DAILSON NOGUEIRA; TEIXEIRA, CAIO JORDAO; MURATA, GILSON MASAHIRO; SANTOS-SILVA, JUNIA CAROLINA; HECHT, FERNANDA BALLERINI; VICENTE, JULIA MODESTO; BORDIN, SILVANA; ANHE, GABRIEL FORATO. Agomelatine reduces circulating triacylglycerides and hepatic steatosis in fructose-treated rats. BIOMEDICINE & PHARMACOTHERAPY, v. 141, SEP 2021. (16/13138-9, 13/07607-8, 15/23285-6, 20/06397-3, 17/20742-2, 19/03196-0)

ALMEIDA, LORENA DE SOUZA; TEIXEIRA, CAIO JORDAO; CAMPOS, CAROLINA VIEIRA; CASALOTI, LAIS GUADALUPE; SODRE, FRHANCIELLY SHIRLEY; CAPETINI, VINICIUS COOPER; AMARAL, ANDRESSA GODOY; PAYOLLA, TANYARA BALIANI; PANTALEAO, LUCAS CARMINATTI; ANHE, GABRIEL FORATO; et al. Low Birth Weight Intensifies Changes in Markers of Hepatocarcinogenesis Induced by Fructose Consumption in Rats. METABOLITES, v. 12, n. 10, p. 15-pg., 2022-10-01. (13/07607-8, 20/13940-5, 19/03196-0, 20/06397-3)

HECHT, FERNANDA BALLERINI; TEIXEIRA, CAIO JORDAO; DE SOUZA, DAILSON NOGUEIRA; NUNES MESQUITA, FILIPHE DE PAULA; DO VAL ROSO, RYANA ELYZABETH; SODRE, FRHANCIELLY SHIRLEY; VERONESI, VANESSA BARBOSA; DA ROCHA, DEBORAH FABIANA; DANTAS DE MENEZES, YAN GUIDA; PIOLI, MARIANA RODRIGUES; et al. Antenatal corticosteroid therapy modulates hepatic AMPK phosphorylation and maternal lipid metabolism in early lactating rats. BIOMEDICINE & PHARMACOTHERAPY, v. 144, DEC 2021. (19/03196-0, 13/07607-8, 20/09717-9, 16/13138-9, 20/06397-3)