Abstract 078: Postnatal Treatment with Metyrapone Attenuates the Effects of Early Life Stress (ELS) on Diet-induced Obesity in Female Rats

Abstract

Clinical studies have shown a positive correlation between ELS and the development of cardiometabolic disease, particularly affecting women. We previously reported that male rats exposed to Maternal Separation (MatSep), a model of ELS in rodents, do not develop exaggerated diet-induced obesity. Thus, this study tested the hypothesis that MatSep exacerbates the response to an obesogenic diet in female rats. Also, we tested whether the postnatal treatment with metyrapone (MTP), a corticosterone synthase inhibitor, would attenuate this phenotype. MatSep was performed in WKY offspring during 3 hours/day from postnatal days 2-14. Non-disturbed littermates were used as controls. Female rat offspring were untreated or treated with MTP (50 mg/kg, i.p.), 30 minutes prior the daily separation. Upon weaning, rats were placed on regular chow (ND, 18% kcal fat) or HFD (60% kcal fat) for 12 weeks. Despite no differences in food intake (metabolism cages) and blood pressure (DSI radiotelemetry) MatSep exaggerated body weight gain and fat pad weights (p<0.05) in response to HFD. Also, MatSep increased plasma corticosterone (189±48 vs. 79±18 pg/ml, p<0.05) and leptin (2.1±0.4 vs. 1.5±0.4 ng/ml, p<0.05) levels compared to control while insulin and adiponectin levels were similar between groups. Oral glucose tolerance test was impaired in MatSep rats showing a greater AUC compared to control rats (p<0.05). Importantly, MTP-treated female MatSep rats showed significantly attenuated diet-induced obesity, glucose intolerance, plasma corticosterone and leptin levels. Histological analysis revealed that MTP treatment ameliorated the adipocyte size in visceral fat from MatSep rats as well (p<0.05). Gene expression in liver indicated that glucose 6 phospatase, but not other gluconeogenic enzymes, were increased in obese MatSep rats, whereas the MTP treatment abrogated this effect. The visceral fat gene expression showed lower levels of insulin receptor in MatSep rats, but no differences in other genes related to the glucose disposal. Overall, these data reveal that female MatSep rats display a greater susceptibility for the synergistic effect between obesogenic diet and ELS compared to male rats, and this effect may be linked to early life exposure to stress hormones.