Perinatal deiodinase 2 expression in hepatocytes defines epigenetic susceptibility to liver steatosis and obesity

Tatiana L. Fonseca, Gustavo W. Fernandes, Elizabeth A. McAninch, Barbara M.L.C. Bocco, Sherine M. Abdalla, Miriam O. Ribeiro, Petra Mohácsik, Csaba Fekete, Daofeng Li, Xiaoyun Xing, Ting Wang, Balázs Gereben, Antonio C. Bianco

Research output: Article

14 Citations (Scopus)

Abstract

Thyroid hormone binds to nuclear receptors and regulates gene transcription. Here we report that in mice, at around the first day of life, there is a transient surge in hepatocyte type 2 deiodinase (D2) that activates the prohormone thyroxine to the active hormone triiodothyronine, modifying the expression of 165 genes involved in broad aspects of hepatocyte function, including lipid metabolism. Hepatocyte-specific D2 inactivation (ALB-D2KO) is followed by a delay in neonatal expression of key lipid-related genes and a persistent reduction in peroxisome proliferator-Activated receptor-γ expression. Notably, the absence of a neonatal D2 peak significantly modifies the baseline and long-Term hepatic transcriptional response to a high-fat diet (HFD). Overall, changes in the expression of approximately 400 genes represent the HFD response in control animals toward the synthesis of fatty acids and triglycerides, whereas in ALB-D2KO animals, the response is limited to a very different set of only approximately 200 genes associated with reverse cholesterol transport and lipase activity. A whole genome methylation profile coupled to multiple analytical platforms indicate that 10-20% of these differences can be related to the presence of differentially methylated local regions mapped to sites of active/suppressed chromatin, thus qualifying as epigenetic modifications occurring as a result of neonatal D2 inactivation. The resulting phenotype of the adult ALB-D2KO mouse is dramatic, with greatly reduced susceptibility to diet-induced steatosis, hypertriglyceridemia, and obesity.

Original languageEnglish
Pages (from-to)14018-14023
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number45
DOIs
Publication statusPublished - nov. 10 2015

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    Fonseca, T. L., Fernandes, G. W., McAninch, E. A., Bocco, B. M. L. C., Abdalla, S. M., Ribeiro, M. O., Mohácsik, P., Fekete, C., Li, D., Xing, X., Wang, T., Gereben, B., & Bianco, A. C. (2015). Perinatal deiodinase 2 expression in hepatocytes defines epigenetic susceptibility to liver steatosis and obesity. Proceedings of the National Academy of Sciences of the United States of America, 112(45), 14018-14023. https://doi.org/10.1073/pnas.1508943112