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

Campos, Carolina Vieira 
Teixeira, Caio Jordão  ORCID logo
Payolla, Tanyara Baliani 
Crisma, Amanda Rabello  ORCID logo
Murata, Gilson Masahiro 

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jats:pIn the present study we investigated the participation of hepatic peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) 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-1α protein content with lower miR-29a-c expression. Increased PGC-1α content was concurrent with increased association to HNF-4α and NRF1 and reduced PPARα 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.</jats:p>

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3101 Biochemistry and Cell Biology, 32 Biomedical and Clinical Sciences, 31 Biological Sciences, Diabetes, Digestive Diseases, Pediatric, Perinatal Period - Conditions Originating in Perinatal Period, Liver Disease
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Fundação de Amparo à Pesquisa do Estado de São Paulo (2013/07607-8, 2014/02977-4, 2016/22605-0, 2019/03196-0, 2020/06397-3, 2020/09717-9)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (001)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (PQ2)