Location: Arkansas Children's Nutrition CenterTitle: Global uterine and blastocyst gene expression patterns associated with maternal overweight at conception) Author
Submitted to: Federation of American Societies for Experimental Biology Conference
Publication Type: Abstract Only
Publication Acceptance Date: 12/15/2010
Publication Date: 4/1/2011
Citation: Shankar, K., Kang, P., Zhong, Y., Andres, A., Ronis, M.J., Badger, T.M. 2011. Global uterine and blastocyst gene expression patterns associated with maternal overweight at conception [abstract]. Proceedings of the Federation of American Societies for Experimental Biology Conference. 990.10. Interpretive Summary: The body composition of the mother at conception and during pregnancy has long-term consequences for the health of the offspring. Using a model of obesity in the rat, we have previously shown 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 the changes in expression of genes in the uterus and the developing embryo to delineate the earliest changes due to maternal obesity. Using microarrays we identified expression of 407 transcripts to be altered in obese dams. Strikingly the expression of inflammatory genes was increased in the obese uterus. Our studies also identified mechanisms leading to increased inflammation orchestrated by Nf-'B. In addition, our studies revealed similarly increased inflammatory gene expression signatures in male blastocysts from obese rat dams. Our results suggest that mechanisms critical in determining the increased predisposition of offspring to obesity may be initiated very early in development.
Technical Abstract: Exposure to maternal overweight (OW) increases the risk of obesity in adult-life. Maternal OW was induced in rats by overfeeding via total enteral nutrition. Male offspring from OW dams gain greater body weight, fat mass and develop insulin resistance when fed high fat diets (45% fat). This is associated with increased lipogenic gene expression in concert with decreased adiponectin-AMPK signaling in the liver at weaning. In this report, we examined the impact of maternal OW on embryonic gene expression in the uterus and peri-implantation blastocysts, using Affymetrix microarrays. Lean and OW female rats were mated with control (lean) breeder males. At 4.5 days post-conception, blastocysts were collected by flushing the uterus and mRNA and genomic DNA was isolated from individual blastocysts (about 70-80 per group). Sex determination was performed using nested PCR for the Y-chromosome and gene expression analysis of blastocysts (of similar gender) was carried out using GeneChip Rat 230 2.0 microarrays (N = 3-4 arrays/group). Uterine gene expression between lean and OW dams was also assessed (N = 6-8 per group) and data analysis performed using GeneSpring Gx 11.0. Exposure to maternal obesity altered 407 transcripts (± 1.3-fold, p < 0.05) in the uterus. GO analyses revealed immune response and chemokine-related functions as most significantly affected. Increased mRNA expression of TLR2, CCL2, CCL5, CxCL10 and Ccr1 (p<0.05) was confirmed by real-time PCR. Blastocyst gene expression was clearly influenced by maternal adiposity (transcripts altered ± 1.4-fold, p < 0.05; 359 in male and 291 in female embryos). Male embryos showed increased expression of proinflammatory genes (CCL4, CCL5) and decreased mRNA of Gpx3. However, the influence of maternal obesity of embryonic gene expression was highly sexually dimorphic (with only about 10% transcripts in common). Our results suggest that mechanisms critical in determining the increased predisposition of offspring to obesity may be initiated very early in development.