Late-pregnancy uterine artery ligation increases susceptibility to postnatal Western diet-induced fat accumulation in adult female offspring

Abstract

Stressors during the fetal and postnatal period affect the growth and developmental trajectories of offspring, causing lasting effects on physiologic regulatory systems. Here, we tested whether reduced uterine artery blood flow in late pregnancy would alter body composition in the offspring, and whether feeding offspring a western diet (WD) would aggravate these programming effects. Pregnant rats underwent bilateral uterine artery ligation (BUAL) or sham surgery on gestational day (GD)18 (term = GD22). At weaning, offspring from each group received either a normal diet (ND) or a WD. BUAL surgery increased fetal loss and caused offspring growth restriction, albeit body weights were no longer different at weaning, suggesting postnatal catch-up growth. BUAL did not affect body weight gain, fat accumulation, or plasma lipid profile in adult male offspring. In contrast, while ND-fed females from BUAL group were smaller and leaner than their sham-littermates, WD consumption resulted in excess weight gain, fat accumulation, and visceral adiposity. Moreover, WD increased plasma triglycerides and cholesterol in the BUAL-treated female offspring without any effect on sham littermates. These results demonstrate that reduced uterine artery blood flow during late pregnancy in rodents can impact body composition in the offspring in a sex-dependent manner, and these effects may be exacerbated by postnatal chronic WD consumption. The last few decades have seen a global rise in the incidence and prevalence of obesity. The World Health Organization estimates that obesity affects 650 million people worldwide, with an additional 1.9 billion classified as overweight 1. Although this trend is attributed, at least in part, to the consumption of energy-rich diets and increasingly sedentary lifestyles, a newly defined contributor to the obesity epidemic is the programming effects caused by stressors during development. The developmental origins of health and disease (DOHaD) theory posits that stressors during the fetal and immediate postnatal period can alter the growth and developmental trajectories of offspring, causing lasting effects on a number of physiologic regulatory systems. Stressors such as hypoxia, anemia, and nutrient imbalances can confer lasting metabolic dysfunction in the offspring, characterized by a propensity for excess fat accumulation 2 , as well as altered glucose metabolism and dyslipidemia 3. Our group has previously characterized a rat model of bilateral uterine artery ligation (BUAL) to reduce uterine artery blood flow, causing antepartum fetal ischemia, growth restriction, and neurodevelopmental outcomes broadly characteristic of cerebral palsy and developmental disability 4,5. The BUAL surgery is performed at gestational day (GD) 18 (term = GD22), and therefore, constitutes a comparatively narrow exposure period of fetal

Gestational Early-Time Restricted Feeding Results in Sex-Specific Glucose Intolerance in Adult Male Mice

“…The extent to which male-specific effects are seen is difficult to deduce as many groups either study male offspring exclusively (34, 35) or analyze males and females together (33, 36). Male offspring who had placental insufficiency develop glucose intolerance in adulthood (37, 38), but females can also develop glucose intolerance (39, 40). Maternal overnutrition can also result in males with glucose intolerance (41, 42).…”