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Title: Alterations in hepatic gene expression and genome-wide DNA methylation in rat offspring exposed to maternal obesity in utero

Author
item BORENGASSER, SARAH - Arkansas Children'S Nutrition Research Center (ACNC)
item ZHONG, YING - Arkansas Children'S Nutrition Research Center (ACNC)
item GOMEZ-ACEVEDO, HORACIO - Arkansas Children'S Nutrition Research Center (ACNC)
item RONIS, MARTIN - Arkansas Children'S Nutrition Research Center (ACNC)
item SHANKAR, KARTIK - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: Federation of American Societies for Experimental Biology Conference
Publication Type: Abstract Only
Publication Acceptance Date: 12/15/2011
Publication Date: 4/1/2012
Citation: Borengasser, S., Zhong, Y., Gomez-Acevedo, H., Ronis, M.J., Shankar, K. 2012. Alterations in hepatic gene expression and genome-wide DNA methylation in rat offspring exposed to maternal obesity in utero. The FASEB Journal. 26(Meeting Abstracts):128.6.

Interpretive Summary: There is an increase in the number of pregnant mothers who are overweight or obese. Childhood obesity is also on the rise and is beginning at younger ages, even as young as infants. This increased prevalence of obesity in mom and children suggest that the fetal environment during pregnancy may be contributing to the obesity epidemic. Using a rat model, we have previously shown that maternal obesity prior to conception leads to the development of obesity-related diseases such as mild insulin resistance, fatty liver, and increased ability to store fat in offspring at weaning as compared to offspring of lean rat dams. In the present studies we investigated whole body and liver metabolism in offspring from lean and obese dams at weaning. We measured energy expenditure, liver gene expression, and changes in global and genome wide methylation. We found that maternal obesity decreased energy expenditure and more specifically, decreased ability to use fat for fuel in the whole body. Further, offspring of obese dams had increased expression of genes associated with fat synthesis and decreased expression of genes associated with fat breakdown in the liver. More specifically, PPAR-alpha, a key regulator of fatty acid breakdown, was hypermethylated in the 3’-UTR region in offspring of obese dams which indicates this gene is more likely to be less active in the liver. In conclusion, maternal obesity appears to contribute to increased weight gain later in life through decreasing specific pathways involved in fat utilization that may be due to an epigenetic modification.

Technical Abstract: Adult offspring from obese (OB) rat dams gain greater body weight and fat mass than controls when fed HFD. At PND21, we examined energy expenditure (EE) (indirect calorimetry), hepatic gene expression (microarrays), and changes in genome-wide and global DNA methylation (enrichment-coupled DNA sequencing, Illumina), coupled with specific signaling pathway analysis. Microarray analyses revealed a reprogramming of lipogenic and lipid degradative pathways as shown by increased expression of SREBP-1 and decreased PPAR-alpha/AMPK signaling. Offspring from OB dams had decreased EE (p<0.05) and higher respiratory exchange ratio values (p<0.05) on AIN-93G or HFD, indicating an impaired capacity to utilize fatty acids (FA). Mitochondrial (mito) protein content of electron transport chain complexes (II, III, and ATPase) was decreased (p<0.03) in OB dam offspring. Hepatic mRNA and mito protein expression of SIRT3, a regulator of mito oxidative capacity and FA oxidation were decreased (p<0.002) in OB dam offspring. Fasting-induced increases in mRNA and protein expression of PGC-1alpha and PPAR-alpha were diminished in OB dam offspring. The 3'-UTR region of PPAR-alpha was hypermethylated in offspring of OB dams consistent with impaired FA mobilization. Maternal obesity influences early hepatic gene expression and DNA methylation. Further, it appears that mito dysfunction precedes the development of excessive weight gain in offspring from OB dams.