Cardiometabolic Phenotypic Differences in Male Offspring Born to Obese Preeclamptic-Like BPH/5 Mice

Abstract

Preeclampsia (PE) is a hypertensive disorder of pregnancy occurring in approximately 10% of women worldwide. While it is life threatening to both the mother and baby, the only effective treatment is delivery of the placenta and fetus, which is often preterm. Maternal obesity is a risk factor for PE, and the effects of both on offspring are long standing with increased incidence of cardiometabolic disease in adulthood. Obese BPH/5 mice spontaneously exhibit excessive gestational weight gain and late-gestational hypertension, similar to women with PE, along with fetal growth restriction and accelerated compensatory growth in female offspring. We hypothesized that BPH/5 male offspring will demonstrate cardiovascular and metabolic phenotypes similar to BPH/5 females. As previously described, BPH/5 females born to ad libitum-fed dams are overweight with hyperphagia and increased subcutaneous, peri-renal, and peri-gonadal white adipose tissue (WAT) and cardiomegaly compared to age-matched adult female controls. In this study, BPH/5 adult male mice have similar body weights and food intake compared to age-matched control mice but have increased inflammatory subcutaneous and peri-renal WAT and signs of cardiovascular disease: left ventricular hypertrophy and hypertension. Therefore, adult male BPH/5 do not completely phenocopy the cardiometabolic profile of female BPH/5 mice. Future investigations are necessary to understand the differences observed in BPH/5 male and female mice as they age. In conclusion, the impact of fetal programming due to PE has a transgenerational effect on both male and female offspring in the BPH/5 mouse model. The maternal obesogenic environment may play a role in PE pregnancy outcomes, including offspring health as they age.

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

“…BPH/5 adult ad libitum fed offspring (AL/AL F ) have evidence of cardiometabolic disease with increased pro‐inflammatory visceral and subcutaneous WAT, hyperleptinemia, and heart enlargement with hypertension versus C57 F controls as previously published (Sutton et al, 2017). BPH/5 AL/AL M have increased visceral and subcutaneous WAT mass versus C57 controls males (Beckers et al, 2021). Prevention of maternal obesity in the PF/AL F and PF/AL M offspring reduces WAT mass in the subcutaneous and visceral WAT depots, and the reproductive WAT is decreased only in BPH/5 PF/AL F (Figure 3a‐c).…”

“…Our BPH/5 dam pair‐feeding paradigm suggests in utero fetal reprogramming of morphometrics to subsequently improve offspring outcomes and prevent obesity into adulthood. Despite similar gestational and postnatal environments, BPH/5 males are not obese nor hyperphagic and do not exhibit hyperleptinemia as females do (Beckers et al, 2021). However, both BPH/5 females and males have heart enlargement, and increased blood pressure (Beckers et al, 2021; Sutton et al, 2017).…”

“…The BPH/5 female offspring present excessive catch up growth after birth, hyperphagia, obesity, cardiomegaly, increased blood pressure, and hyperleptinemia with leptin resistance (Sutton et al, 2017). However, the adult male BPH/5 offspring are not hyperphagic and are not obese, but do exhibit increased white adipose tissue mass and cardiomegaly with left ventricular hypertrophy (Beckers et al, 2021).…”

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

“…Additionally, BPH/5 offspring are affected by intrauterine growth restriction, evidenced by fetal demise, smaller litter sizes, and marked decrease in birth weight when compared to C57 controls (Davisson et al, 2002). Postnatally, excessive compensatory growth from birth to early adulthood has been reported in BPH/5 females, but not males (Sutton et al, 2017;Beckers et al, 2021). Specifically, while BPH/5 females are smaller Frontiers in Physiology frontiersin.org than C57 controls at postnatal day 1, no difference in body weight is seen at 3 weeks of age, and higher body weight is displayed by 8-week-old BPH/5 females (Sutton et al, 2017).…”

“…BPH/5 females are spontaneously obese, dyslipidemic, hyperleptinemic, hyperphagic and hypertensive, a phenotype exacerbated during pregnancy ( Davisson et al, 2002 ; Reijnders et al, 2019 ; Sones et al, 2021 ). Even though long-term adverse outcomes occur in both BPH/5 male and female offspring, a sexually dimorphic cardiometabolic phenotype has been elucidated ( Sutton et al, 2017 ; Beckers et al, 2021 ). 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 ).…”