Sex‐specific effects of maternal weight loss on offspring cardiometabolic outcomes in the obese preeclamptic‐like mouse model, BPH/5

Abstract

Preeclampsia (PE) is a hypertensive disorder that impacts 2–8% of pregnant women worldwide. It is characterized by new onset hypertension during the second half of gestation and is a leading cause of maternal and fetal morbidity/mortality. Maternal obesity increases the risk of PE and is a key predictor of childhood obesity and potentially offspring cardiometabolic complications in a sex‐dependent manner. The influence of the maternal obesogenic environment, with superimposed PE, on offspring development into adulthood is unknown. Obese BPH/5 mice spontaneously exhibit late‐gestational hypertension, fetal demise and growth restriction, and excessive gestational weight gain. BPH/5 females have improved pregnancy outcomes when maternal weight loss via pair‐feeding is imposed beginning at conception. We hypothesized that phenotypic differences between female and male BPH/5 offspring can be influenced by pair feeding BPH/5 dams during pregnancy. BPH/5 pair‐fed dams have improved litter sizes and increased fetal body weights. BPH/5 offspring born to ad libitum dams have similar sex ratios, body weights, and fecal microbiome as well as increased blood pressure that is reduced in the dam pair‐fed offspring. Both BPH/5 male and female offspring born to pair‐fed dams have a reduction in adiposity and an altered gut microbiome, while only female offspring born to pair‐fed dams have decreased circulating leptin and white adipose tissue inflammatory cytokines. These sexually dimorphic results suggest that reduction in the maternal obesogenic environment in early pregnancy may play a greater role in female BPH/5 sex‐dependent cardiometabolic outcomes than males. Reprograming females may mitigate the transgenerational progression of cardiometabolic disease.

Sexually dimorphic pubertal development and adipose tissue kisspeptin dysregulation in the obese and preeclamptic-like BPH/5 mouse model offspring

“…Weight loss was induced in a cohort of non-pregnant adult BPH/5 females using a feeding paradigm previously established in this mouse model ( Reijnders et al, 2019 ; Beckers et al, 2022 ). Briefly, the diet was restricted to 3 g of rodent standard chow (Purina 5001, Neenah, WI) per day for a total of 7 days.…”

“…Briefly, the diet was restricted to 3 g of rodent standard chow (Purina 5001, Neenah, WI) per day for a total of 7 days. With this diet, pair-fed BPH/5 females (BPH/5 PF) are expected to consume 25% less calories than ad libitum-fed counterparts (BPH/5 AL), matching the food intake of lean, ad libitum-fed, C57 controls ( Reijnders et al, 2019 ; Beckers et al, 2022 ). The non-pregnant pair-fed females were humanely euthanized the day after completion of the 7-day diet and sample collection was performed.…”

“…Interestingly, while the obese phenotype is perpetuated in BPH/5 female offspring, BPH/5 males do not present increased food intake, body weight, or reproductive white adipose tissue (rWAT) mass in comparison to controls ( Sutton et al, 2017 ; Beckers et al, 2021 ). Importantly, the influence of obesity in the preeclamptic-like phenotype of the BPH/5 mouse model has been clearly established ( Reijnders et al, 2019 ; Beckers et al, 2022 ). Of interest, maternal weight loss via a pair-feeding paradigm not only attenuates the BPH/5 mouse maternal inflammatory milieu and pregnancy outcomes, but also improves long-term consequences in the offspring in a sex-specific manner ( Reijnders et al, 2019 ; Beckers et al, 2022 ).…”

“…Importantly, the influence of obesity in the preeclamptic-like phenotype of the BPH/5 mouse model has been clearly established ( Reijnders et al, 2019 ; Beckers et al, 2022 ). Of interest, maternal weight loss via a pair-feeding paradigm not only attenuates the BPH/5 mouse maternal inflammatory milieu and pregnancy outcomes, but also improves long-term consequences in the offspring in a sex-specific manner ( Reijnders et al, 2019 ; Beckers et al, 2022 ).…”

“…It was hypothesized that BPH/5 progeny would present abnormal pubertal development when compared to C57BL/6 (C57) control mice. Furthermore, the sexually dimorphic obese phenotype of the BPH/5 mouse was further explored, and a potential link between nutrition, rWAT kisspeptin expression and sex steroid hormone profile was explored, utilizing the well-established BPH/5 pair-feeding paradigm ( Reijnders et al, 2019 ; Beckers et al, 2022 ).…”