Changes in PGC-1α-Dependent Mitochondrial Biogenesis Are Associated with Inflexible Hepatic Energy Metabolism in the Offspring Born to Dexamethasone-Treated Mothers

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Campos, Carolina Vieira ; Teixeira, Caio Jordao ; Payolla, Tanyara Baliani ; Crisma, Amanda Rabello ; Murata, Gilson Masahiro ; Amaral, Andressa Godoy ; Pantaleao, Lucas Carminatti ; Sodre, Frhancielly Shirley ; Onari, Mariana Mayumi ; Almeida, Lorena de Souza ; Pereira, Gizela A. ; Guimaraes, Dimitrius Santiago Simoes Froes ; Silveira, Leonardo Reis ; Anhe, Gabriel Forato ; Bordin, Silvana

• Document type: Journal article
• Source: LIVERS; v. 1, n. 4, p. 20-pg., 2021-12-01.

Abstract

In the present study we investigated the participation of hepatic peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha) in the metabolic programming of newborn rats exposed in utero to dexamethasone (DEX). On the 21st day of life, fasted offspring born to DEX-treated mothers displayed increased conversion of pyruvate into glucose with simultaneous upregulation of PEPCK (phosphoenolpyruvate carboxykinase) and G6Pase (glucose-6-phosphatase). Increased oxidative phosphorylation, higher ATP/ADP ratio and mitochondrial biogenesis and lower pyruvate levels were also found in the progeny of DEX-treated mothers. On the other hand, the 21-day-old progeny of DEX-treated mothers had increased hepatic triglycerides (TAG) and lower CPT-1 activity when subjected to short-term fasting. At the mechanistic level, rats exposed in utero to DEX exhibited increased hepatic PGC-1 alpha protein content with lower miR-29a-c expression. Increased PGC-1 alpha content was concurrent with increased association to HNF-4 alpha and NRF1 and reduced PPAR alpha expression. The data presented herein reveal that changes in the transcription machinery in neonatal liver of rats born to DEX-treated mothers leads to an inflexible metabolic response to fasting. Such programming is hallmarked by increased oxidative phosphorylation of pyruvate with impaired FFA oxidation and hepatic TAG accumulation. (AU)

• FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
• Grantee: Licio Augusto Velloso
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 16/23008-5 - Identification and functional characterization of protein bound to NCoR1 complex and associated with molecular control of mitochondrial biogenesis process
• Grantee: Leonardo dos Reis Silveira
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 20/09717-9 - Molecular mechanisms involved in cardiovascular changes triggered by fetal excess glucocorticoids
• Grantee: Frhancielly Shirley Souza Sodré
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 20/06397-3 - Study of cellular senescence in rodents subjected to Obesity
• Grantee: Caio Jordão Teixeira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/03196-0 - Molecular mechanisms involved in the metabolic inflexibility of rats submitted to metabolic programming induced by prenatal excess of glucocorticoids
• Grantee: Silvana Auxiliadora Bordin da Silva
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/02977-4 - Epigenetic mechanisms associated with obesity and chronic inflammation
• Grantee: Amanda Rabello Crisma
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/22605-0 - Epigenetic regulation of PGC-1a expression in the liver of offspring subjected to antenatal exposure to glucocorticoids
• Grantee: Carolina Vieira Campos
• Support Opportunities: Scholarships in Brazil - Scientific Initiation