Perinatal deiodinase 2 expression in hepatocytes defines epigenetic susceptibility to liver steatosis and obesity.
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.
Division of Endocrinology and Metabolism, Rush University Medical Center, Chicago, IL 60612;
Tatiana L
TL
Fonseca
Division of Endocrinology and Metabolism, Rush University Medical Center, Chicago, IL 60612; Translational Medicine, Federal University of São Paulo, São Paulo 04023-900, SP, Brazil;
Gustavo W
GW
Fernandes
Division of Endocrinology and Metabolism, Rush University Medical Center, Chicago, IL 60612;
Elizabeth A
EA
McAninch
Division of Endocrinology and Metabolism, Rush University Medical Center, Chicago, IL 60612; Translational Medicine, Federal University of São Paulo, São Paulo 04023-900, SP, Brazil;
Barbara M L C
BM
Bocco
Department of Medicine, University of Miami Miller School of Medicine, Miami, FL; 33136;
Sherine M
SM
Abdalla
Developmental Disorders Program, Center of Biological Science and Health, Mackenzie Presbyterian University, São Paulo 01302-907, SP, Brazil;
Miriam O
MO
Ribeiro
Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083 Budapest, Hungary; János Szentágothai School of Neurosciences, Semmelweis University, 1085 Budapest, Hungary;
Petra
P
Mohácsik
Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083 Budapest, Hungary; Division of Endocrinology, Diabetes and Metabolism, Tufts Medical Center, Boston, MA 02116;
Csaba
C
Fekete
Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63108.
Daofeng
D
Li
Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63108.
Xiaoyun
X
Xing
Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63108.
Ting
T
Wang
Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083 Budapest, Hungary;
Balázs
B
Gereben
Division of Endocrinology and Metabolism, Rush University Medical Center, Chicago, IL 60612; abianco@deiodinase.org.
Antonio C
AC
Bianco
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002153:Calorimetry, Indirect; D019175:DNA Methylation; D059305:Diet, High-Fat / Q000009:adverse effects; D004198:Disease Susceptibility / Q000201:enzymology*; D005234:Fatty Liver / Q000201:enzymology* / Q000209:etiology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D022781:Hepatocytes / Q000378:metabolism*; D017403:In Situ Hybridization; D007453:Iodide Peroxidase / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D009765:Obesity / Q000201:enzymology* / Q000209:etiology; D014284:Triiodothyronine / Q000097:blood
D014284:Triiodothyronine; D007453:Iodide Peroxidase
deiodinase; lipids; obesity; steatosis; thyroid hormone