|Shankar, Kartik -|
|Zhong, Ying -|
|Kang, Ping -|
|Lau, Franchesca -|
|Blackburn, Michael -|
|Chen, Jinran -|
|Borengasser, Sarah -|
|Ronis, Martin -|
Submitted to: Journal of Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: July 29, 2011
Publication Date: November 1, 2011
Citation: Shankar, K., Zhong, Y., Kang, P., Lau, F., Blackburn, M.L., Chen, J., Borengasser, S., Ronis, M.J., Badger, T.M. 2011. Maternal obesity promotes a proinflammatory signature in rat uterus and blastocyst. Journal of Endocrinology. 152(11):4158-4170. 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-kappa 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 maybe initiated very early in development.
Technical Abstract: Maternal obesity at conception increases the risk of offspring obesity, thus propagating an intergenerational vicious cycle. Male offspring born to obese dams are hyper-responsive to high fat diets, gaining greater body weight, fat mass and additional metabolic sequelae compared to lean controls. In this report, we identify the impact of maternal obesity prior to conception, on the embryo and intrauterine milieu during the peri-implantation period. We conducted global transcriptomic profiling in the uterus and peri-implantation blastocyst, gene/protein expression analyses of inflammatory pathways in conjunction with endocrine and metabolic characterization in the dams at implantation. Uterine gene expression profiles of lean and obese dams revealed distinct signatures for genes regulating inflammation and lipid metabolism. Both pathway and GSEA revealed uterine NF-kappa B and JNK signaling to be up-regulated in the uterus of obese dams, which was confirmed via immunoblotting. Obese uteri also evidenced an inflammatory secretome with higher chemokine mRNA abundance (CCL2, CCL5, CCL7, CxCL10) and related regulators (TLR2, CD14, Ccr1). Increased inflammation in the uterus was associated with ectopic lipid accumulation and expression of lipid metabolic genes. Gene expression in sex-identified male peri-implantation blastocyst at dpc 4.5 was clearly influenced by maternal obesity (359 transcripts, +/- 1.4-fold) including changes in developmental and epigenetic regulators. Akin to the uterus, NF-kappa B-regulated proinflammatory genes (CCL4, CCL5) increased and expression of antioxidant (GPx3) and mitochondrial (TFAM, NRF1) genes decreased in the obese embryos. Our results suggest that ectopic lipid and inflammation may link maternal obesity to increased predisposition of offspring to obesity later in life.