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Title: Early growth response protein-1 mediates lipotoxicity-associated placental inflammation: Role in maternal obesity

Author
item SABEN, JESSICA - 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 THAKALI, KESHARI - Arkansas Children'S Nutrition Research Center (ACNC)
item BORENGASSER, SARAH - Arkansas Children'S Nutrition Research Center (ACNC)
item ANDRES, ALINE - Arkansas Children'S Nutrition Research Center (ACNC)
item SHANKAR, KARTIK - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/29/2013
Publication Date: 7/1/2013
Citation: Saben, J., Zhong, Y., Gomez-Acevedo, H., Thakali, K.M., Borengasser, S.J., Andres, A., Shankar, K. 2013. Early growth response protein-1 mediates lipotoxicity-associated placental inflammation: Role in maternal obesity. American Journal of Physiology - Endocrinology and Metabolism. 305(1):E1-E14.

Interpretive Summary: A low level of chronic inflammation is present in obese individuals as a result of increased adipose tissue, and this can perpetuate the development of metabolic disease. During pregnancy, increased amounts of inflammatory markers have been observed in obese women, which may contribute to changes in placenta function affecting fetal growth and metabolism. The factors contributing to increased inflammation in obese placenta are yet to be determined. We used a cell culture model of human placenta cells to test whether saturated fatty acids and/or inflammatory molecules are able to increase inflammation. Our data show that both saturated fatty acid and inflammatory molecules induce the expression of inflammatory genes in human placenta cells and that when these treatments are combined, they result in an exaggerated inflammatory response. Furthermore, when we examined placenta tissue from obese and lean subjects we found similar changes in inflammatory markers as observed in vitro. Our results indicate that increased circulating saturated fatty acids and inflammatory molecules associated with obesity may contribute to inflammation in placenta cells.

Technical Abstract: Obesity is associated with low-grade chronic inflammation, which contributes to cellular dysfunction promoting metabolic disease. Obesity during pregnancy leads to a pro-inflammatory milieu in the placenta; however, the underlying causes for obesity-induced placental inflammation remain unclear. Herein we examine the mechanisms by which saturated fatty acids and inflammatory cytokines induce inflammation in placental trophoblasts. We conducted global transcriptomic profiling in BeWo cells following palmitate and/or TNF alpha treatment, gene/protein expression analyses of MAPK pathways, and characterized downstream transcription factors directly regulating inflammatory cytokines. Microarray analysis revealed increased expression of genes regulating inflammation, stress response, and immediate-early response in cytotrophoblasts in response to palmitic acid (PA), TNF alpha, or a combination of both (PA + TNF alpha). Both gene-ontology and gene-set enrichment analysis revealed MAPK and EGR-1 signaling to be up-regulated in BeWo cells, which was confirmed via immunoblotting. Importantly, activation of JNK signaling was necessary for increased pro-inflammatory cytokine (IL-6, TNF alpha, IL-8) and EGR1 mRNA. Consistent with the requirement of JNK signaling, ChIP analysis confirmed the recruitment of c-Jun and other MAPK-responsive immediate early factors on EGR1 promoter. Moreover, recruitment of EGR-1 on cytokine promoters (IL-6, TNF alpha, IL-8) and an impaired pro-inflammatory response following knockdown of EGR1 suggested it as a central component of the mechanism facilitating inflammatory gene expression. Finally, akin to in vitro findings, term placenta from obese women also had both increased JNK and p38 signaling, and greater EGR-1 protein relative to lean women. Our results demonstrate that lipotoxic insults induce inflammation in placental cells via activation of JNK-EGR-1 signaling.