High Fat Diet‐Induced Maternal Obesity Programs Senescence Signaling and Glucose Metabolism in Rat Embryonic Osteoblastic Cells

Abstract

Epidemiological studies suggest that diet quality and nutritional status in utero and early postnatal life influence the risk of chronic diseases. However, evidence on the impact of gestational events on regulation of bone development is sparse. We have studied fetal bone development in lean and high fat diet (HFD)-induced obese rat dams. To generate a maternal obesity model, we fed female rats with HFD containing 45% fat for 10 wk starting at 8 wk of age. Rats were then impregnated and diets were continued to the end of the experiment (dpc 18.5). We present evidence that fetal osteogenic calvarial cells (FOCC) from obese rat dams have significantly increased levels of Enhancer of zeste homologue 2 (EZH2) mRNA and protein compared to cells from AIN-93G diet-fed controls. CDK1 expression and phosphorylation of EZH2 were significantly lower in FOCCs from obese rat dams fed a HFD compared to FOCCs from control diet dams. Using chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq), we show epigenetic regulation of polycomb-regulated genes in FOCC from obese dams. In synergy with increased repressive histone mark of H3K27me3 of IGF1 and TFap2, decreased H3K27me3 of BMP4 leads to increased cell senescence signaling in FOCCs. Furthermore, independent of BMP4, EGR1- and p53/p21-mediated increase of cell senescence signaling but decreased aerobic glycolysis was imprinted in HFD-FOCCs resulting in less potential of osteoblast differentiation. These findings suggest programming of fetal pre-osteoblastic cell senescence and glucose metabolism by maternal obesity. Supported by ARS CRIS #6251-51000-005-03S.