Location: Arkansas Children's Nutrition CenterTitle: Maternal obesity influences hepatic gene expression and genome-wide DNA methylation in offspring liver at weaning Author
Submitted to: Journal of Developmental Origins of Health and Disease
Publication Type: Abstract Only
Publication Acceptance Date: 7/1/2011
Publication Date: 9/1/2011
Citation: Shankar, K., Borengasser, S.J., Zhong, Y., Gomez-Acevedo, H., Ronis, M.J., Badger, T.M. 2011. Maternal obesity influences hepatic gene expression and genome-wide DNA methylation in offspring liver at weaning. Journal of Developmental Origins of Health and Disease. Vol 2(S1):pp S2-S34. Abstract#0-2v-3. Interpretive Summary: Maternal body composition at conception has long-term consequences for the health of the offspring. We have studied whether in utero exposure to maternal obesity increases the risk of obesity in the offspring in later-life using a model of obesity in the rat. Our initial results strongly suggested that maternal obesity via metabolic factors independent of genetic influences leads to increased risk of obesity in the offspring when challenged with a high fat diet. In the present studies we investigated changes in expression of genes in the liver of offspring at weaning prior to development of obesity. Genes related to synthesis of new lipids (lipogenic) were increased while those involved in oxidation of lipids were decreased in offspring born to obese dams. We identified a key epigenetic regulator SIRT3, critical of mitochondrial fatty acid oxidation to be down-regulated in offspring of obese dams. Examination of energy expenditure, revealed that offspring of obese dams, have modestly lower energy expenditure and greater reliance on carbohydrate relative to fatty acids. Finally our studies examined changes in DNA methylation in the offspring liver, that may underlie the metabolic abnormalities in obese-dam offspring. Our findings suggest that maternal obesity may program the responsiveness in the offspring of overweight dams and hence may increase susceptibility to weight gain and obesity.
Technical Abstract: Offspring from obese rat dams gain greater body weight and fat mass when fed HFD. Here we examine hepatic gene expression related to systemic energy expenditure and alterations in genome-wide DNA methylation. Maternal obesity was produced in rats prior to conception via overfeeding of diets. At PND21, we examined energy expenditure (indirect calorimetry), hepatic gene expression (microarrays), and changes in genome-wide DNA methylation (enrichment-coupled sequencing, Illumina), coupled with specific signaling pathway analysis. Results: Microarray analyses at PND 21 revealed a reprogramming of lipogenic and lipid degradative pathways. This was associated with increased expression of SREBP-1 and 20 lipogenic effectors, and decreased PPAR-a/AMPK signaling. Offspring from obese dams had decreased energy expenditure (p<0.05) and higher respiratory exchange ratio values (p<0.05) on either AIN-93G or HFD, indicating an impaired capacity to utilize fatty acids(FA). Mitochondrial protein content of electron transport chain complexes (II, III, and ATPase) was decreased (p<0.03) in offspring from obese dams. Hepatic mRNA and mitochondrial protein expression of SIRT3, an critical regulator of mitochondrial oxidative capacity and FA oxidation were decreased (p<0.002) in offspring from obese dams. Fasting-induced increases in mRNA and protein expression of PGC-1 alpha and PPAR-alpha were significantly diminished in offspring of obese dams. Finally, we employed a procedure to enrich methylated DNA using capture with methylbinding protein followed by Illumina sequencing. MACS analysis identified more than 4,000 differentially methylated regions. Following classification of the regions based on CpG content (cut-off > 3%), and +/- 5 Kb window of annotation, 799 genes were identified with differentially methylated regions. Based on this analysis, the 3'-UTR region of PPAR-alpha was found to be hypermethylated in offspring of obese dams consistent with impaired fatty acid mobilization. Maternal obesity influences early hepatic gene expression and DNA methylation. Further it appears that mitochondrial dysfunction precedes the development of energy utilization perturbations, hepatic steatosis and adiposity in offspring from obese rat dams.