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 de- lay 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 ani- mals, the response is limited to a very different set of only approx- imately 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 re- gions mapped to sites of active/suppressed chromatin, thus qualify- ing 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 stea- tosis, hypertriglyceridemia, and obesity.
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, and Antonio C. Bianco. PNAS. September 21, 2015. PMID: 26508642