Although sex biases in disease presentation are well documented, the mechanisms mediating vulnerability or resilience to diseases are unknown. In utero insults are more likely to produce detrimental health outcomes for males versus females. In our mouse model of prenatal stress, male offspring experience long-term dysregulation of body weight and hypothalamic pituitary adrenal stress axis dysfunction, endophenotypes of male-biased neurodevelopmental disorders. Placental function is critical for healthy fetal development, and we previously showed that sex differences in placental O-linked N-acetylglucosamine transferase (OGT) mediate the effects of prenatal stress on neurodevelopmental programming. Here we show that one mechanism whereby sex differences in OGT confer variation in vulnerability to prenatal insults is by establishing sex-specific trophoblast gene expression patterns and via regulation of the canonically repressive epigenetic modification, H3K27me3. We demonstrate that high levels of H3K27me3 in the female placenta create resilience to the altered hypothalamic programming associated with prenatal stress exposure. Copyright 2018 The Author(s).

Objective To determine the 6‐month follow‐up effects after intentional 6‐month weight loss alone (WL) and after weight loss with aerobic exercise (AEX + WL) on body composition, glucose metabolism, and cardiovascular disease risk factors in older postmenopausal women and to identify the mechanisms for weight regain. Methods Women (n = 65, BMI > 25 kg/m2) underwent maximal oxygen consumption testing, dual‐energy x‐ray absorptiometry, computed tomography scans, and oral glucose tolerance tests before and after 6 months of AEX + WL or WL and at 12 months ad libitum follow‐up. Insulin sensitivity (M) (hyperinsulinemic‐euglycemic clamp) was measured at baseline and 6 months. Thirty WL and thirty‐five AEX + WL women completed a follow‐up at 12 months. Results Similar weight loss was observed (−8%) in both groups from 0 to 6 months. Total fat mass, fat‐free mass, visceral fat area, subcutaneous abdominal and midthigh fat areas, fasting glucose, insulin levels, homeostatic model assessment of insulin resistance (HOMA‐IR), insulin areas under the curve, and triglyceride levels decreased similarly after WL and AEX + WL and remained lower at 12 months than at baseline, despite weight regain at 12 months. Initial M was associated with weight regain (r = −0.40, P < 0.01). Weight regain was related to independent changes in leptin and HOMA‐IR from 6 to 12 months in a multiple regression model (r = 0.77, P < 0.0001). Conclusions Reductions in body fat and improvements in insulin sensitivity after AEX + WL and WL were maintained at 12 months despite modest weight regain. Baseline insulin resistance partially predicted the magnitude of weight regain in postmenopausal women. Copyright 2017 The Obesity Society