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.
Preeclampsia (PE) is a devastating gestational syndrome responsible for maternal and fetal morbidity/mortality. Maternal obesity and dyslipidemia are PE risk factors and adipokines may play a central role in the etiopathogenesis. Features of PE are spontaneously recapitulated by the blood pressure high subline 5 (BPH/5) mouse, including hypertension, obesity, and dyslipidemia in females before and throughout pregnancy. We have reported a sexually dimorphic phenotype in adult BPH/5: females are hyperphagic and overweight with increased reproductive white adipose tissue (rWAT), while males have similar food intake, body weight (BW) and rWAT mass as controls. Moreover, BPH/5 fed a 25% calorie restricted diet (CR) during the first 7 days (d) of gestation have reduced BW, rWAT mass, and ameliorated inflammatory milieu and adverse pregnancy outcomes. Kisspeptins (KP) are small peptides originated from the Kiss1 gene. Dysregulation of Kiss1 and the KP receptor (Kiss1r) have been suggested in PE. Similarly, BPH/5 have Kiss1/Kiss1r misexpression at the maternal‐fetal interface. Besides their role in the hypothalamus and placenta, Kiss1/Kiss1r are also expressed in adipose tissue, with potential roles in metabolism, energy expenditure, thermoregulation and adipogenesis. When fed normal diet, adult female kiss1r‐knockout (KO) mice have reduced energy expenditure, increased adiposity and BW, while adult male Kiss1r‐KO have increased adiposity but similar BW than wild‐type littermates. Hence, we aimed to characterize Kiss1/Kiss1r expression in the rWAT of adult male and non‐pregnant female BPH/5. It was hypothesized that rWAT Kiss1/Kiss1r mRNA expression will be lower in the obese females when compared to control C57, but not different between adult male BPH/5 and C57. Furthermore, feeding a 25% CR diet for 7 days to non‐pregnant BPH/5 females was expected to attenuate Kiss1/Kiss1r downregulation. To test our hypothesis, rWAT was collected from adult ad libitum‐fed BPH/5 and C57 males (n=3‐4/group), non‐pregnant females (n = 5‐6/group) and BPH/5 non‐pregnant females after 7 d of 25% CR (n = 5‐6/group). Kiss1/Kiss1r mRNA was measured using RT‐PCR and comparisons were made using independent samples t‐test (SPSS) with significance at p < 0.05. Non‐pregnant adult BPH/5 females had 55‐ and 1.5‐fold lower Kiss1 and Kiss1r in rWAT, respectively, when compared to C57 (p < 0.05). In males, rWAT Kiss/Kiss1r levels were not different between BPH/5 and C57 (p > 0.05). There was no difference in Kiss1r rWAT in BPH/5 females fed ad libitum vs. 25% CR diet (p > 0.05). However, rWAT Kiss1 expression was 16‐fold higher in 25% CR BPH/5 than BPH/5 fed ad libitum (p < 0.05). In conclusion, there is a sexual dimorphism in rWAT Kiss1/Kiss1r expression in BPH/5 mice, with lower levels associated with the obese phenotype of females. When fed a 7d 25% CR diet, rWAT Kiss1 levels increase, which may be associated with the reduced BW and adiposity seen in these females. Further studies are needed to investigate the KP‐associated pathways in the adipose ...
Preeclampsia (PE) is a hypertensive disorder of pregnancy with an incompletely understood etiology affecting approximately 10% of pregnancies worldwide. Obesity is a risk factor among women that develop PE and is mirrored in the blood pressure high subline 5 (BPH/5) mouse. Before pregnancy, BPH/5 adult females are hyperphagic, obese and dyslipidemic with increased reproductive white adipose tissue (rWAT) that expands throughout pregnancy, along with other PE‐like symptoms. Pregnant BPH/5 females develop poor placentation with decreased trophoblast invasion and inadequately remodeled decidual vessels, a recognized feature of PE. Kisspeptins (KP), a family of small peptides encoded by the Kiss1 gene, are important regulators of cellular migration and proliferation. They have been shown to inhibit the migration and invasion of trophoblast cells in humans and rodents and may be involved in abnormal placentation observed in PE. Interestingly, Kiss1/Kiss1r are also expressed in the adipose tissue with a potential role in metabolism regulation, including inhibition of adipogenesis and lipolysis induction. When fed a normal diet, adult female kiss1r‐knockout mice have reduced energy expenditure, increased adiposity and body weight (BW) than wild‐type littermates. Hence, we aimed to characterize Kiss1/Kiss1r mRNA expressionin BPH/5 rWAT and the uteroplacental interface at the peak of decidualization. We hypothesized that at embryonic day (e) 7.5, Kiss1/Kiss1r will be higher in BPH/5 implantation sites, but lower in the rWAT, when compared to control C57. Furthermore, we hypothesized that feeding BPH/5 dams a 25% calorie restriction (CR) diet, beginning at conception (e0.5), would normalize the Kiss1/Kiss1r in e7.5 implantation sites and rWAT. To test our hypothesis, implantation sites and rWAT were collected at e7.5 from adult BPH/5 and C57 fed ad libitum, and age‐matched e7.5 BPH/5 females after 25% CR from e0.5 to e7.5 (n = 5‐9/group). Kiss1/Kiss1r were measured using RT‐PCR and comparisons were performed using independent samples t‐test (SPSS) with significance set at 5%. BPH/5 e7.5 implantation sites had 2‐fold higher Kiss1/Kiss1r when compared to C57 (p < 0.05). In the rWAT, Kiss1 was approximately five‐fold lower in BPH/5 vs. C57 (p < 0.05). When considering Kiss1r, however, the expression was 1.5‐fold higher in BPH/5 vs. C57 (p < 0.05). When comparing ad libitum BPH/5 and 25% CR BPH/5 females at e7.5, there was no difference in the rWAT Kiss1/Kiss1r (p > 0.05). Therefore, upregulation of Kiss1/Kiss1r at the utero‐placental interface during the peak of decidualization, along with increased Kiss1r in the rWAT characterizes the BPH/5 model of PE. Concurrently, the Kiss1 levels are lower in the BPH/5 rWAT at e7.5 and may be associated with the increased adiposity of these mice previously shown throughout gestation. Even though 7 days of 25% CR has been previously shown to decrease the body weight of pregnant BPH/5 females, it did not alter the expression levels of Kiss1/Kiss1r in the rWAT at e7.5. Further studies are n...
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