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Title: Inhibition of fetal bone development through epigenetic down- regulation of HoxA10 in obese rats fed high fat diet

Author
item CHEN, JINRAN - Arkansas Children'S Nutrition Research Center (ACNC)
item ZHANG, JIAN - Arkansas Children'S Nutrition Research Center (ACNC)
item LAZARENKO, OXANA - Arkansas Children'S Nutrition Research Center (ACNC)
item KANG, PING - Arkansas Children'S Nutrition Research Center (ACNC)
item BLACKBURN, MICHAEL - Arkansas Children'S Nutrition Research Center (ACNC)
item RONIS, MARTIN - Arkansas Children'S Nutrition Research Center (ACNC)
item Badger, Thomas - Arkansas Children'S Nutrition Research Center (ACNC)
item SHANKAR, KARTIK - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: Journal of Federation of American Societies for Experimental Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/14/2011
Publication Date: 3/1/2012
Citation: Chen, J., Zhang, J., Lazarenko, O.P., Kang, P., Blackburn, M.L., Ronis, M.J., Badger, T.M., Shankar, K. 2012. Inhibition of fetal bone development through epigenetic down- regulation of HoxA10 in obese rats fed high fat diet. Journal of Federation of American Societies for Experimental Biology. 26(3):1131-1141.

Interpretive Summary: Previous studies show that obesity during pregnancy or in early life increases the risk of low bone quality and fracture later in adult. Here, we show that bone development is inhibited in gestational day 18.5 fetus from rat moms made obese by feeding a high fat diet (HFD). Moreover, fetal rat bone forming cells isolated from these obese dams have significantly less potential to develop into mature functional bone cells compared to cells from control AIN-93G diet-fed animals. We found that expression level of a gene, previously call homeodomain-containing factor A10 (HoxA10), was profoundly decreased in the bone forming cells isolated from these obese dams. In vitro culture confirmed our in vivo animal study. Future more, we found that HoxA10 gene may control balance between fat and bone formation during fetal life. These results suggest that obesity in moms impairs fetal bone development through down regulation of the HoxA10 gene which may lead to an increase in the prevalence of low bone mass in their offspring later in life.

Technical Abstract: Epidemiological studies show that maternal obesity during intrauterine and early postnatal life increases the risk of low bone mass and fracture later in life. Here, we show that bone development is inhibited in GED 18.5 embryos from rat dams made obese by feeding a high fat diet (HFD). Moreover, fetal rat osteogenic calvarial cells (FOCCs) from these obese dams have significantly less potential to develop into mature osteoblasts compared to cells from AIN-93G diet-fed controls. Profiling of transcriptional genes for osteogenesis revealed a profound decrease in the homeodomain-containing factor A10 (HoxA10) in FOCCs from fetuses of HFD-induced obese dams. Significant methylation of the HoxA10 promoter was found in those FOCCs, as well as in mouse ST2 cells treated with a mixture of free fatty acids similar to that found in serum from HFD-induced obese rats. This was accompanied by lower expression of osteogenic markers, but higher levels of PPAR gamma. Control FOCCs depleted of the HoxA10 gene (shRNA) ex vivo behave similarly to cells from fetus of obese dams, conversely over expression of HoxA10 gene in FOCCs from HFD rats exhibit the same phenotype as controls. Treatment of FOCCs from control rats or of ST2 cells with an artificial mixture of free fatty acids significantly down-regulated HoxA10 protein expression, and cells exhibited adipocyte-like properties. These results suggest that maternal obesity impairs fetal skeletal development through down regulation of the HoxA10 gene which may lead to an increase in the prevalence of low bone mass in their offspring later in life.