Effects of maternal calorie restriction on inflammatory mediators in male offspring of preeclamptic‐like BPH/5 mice

Abstract

Preeclampsia (PE) is characterized by maternal hypertension after 20 weeks of gestation coupled with clinical signs such as proteinuria, thrombocytopenia, hepatic dysfunction, and/or pulmonary edema. Women with pre-existing obesity are 3 times more likely to develop PE. Even though PE is a leading cause of maternal and fetal morbidity and mortality, the long-term impact of the maternal obesogenic environment on the offspring is not completely understood. To investigate this, we utilized the obese BPH/5 mouse, which spontaneously develops hypertension and excessive gestational weight gain early in pregnancy. We have previously shown that calorie restricted pregnant BPH/5 females have improved outcomes when pair-feeding is imposed beginning at the time of conception, embryonic day (e) 0.5, including increased live birth weight and litter sizes, and attenuation of pro-inflammatory cytokines at the maternal-fetal interface compared to BPH/5 ad libitum fed pregnancies. We hypothesized that pair-feeding BPH/5 mice during pregnancy will improve cardiometabolic outcomes in adult BPH/5 males. To test our hypothesis, we first phenotyped adult BPH/5 and control C57 male mice that gestated in ad libitum fed dams. Unlike BPH/5 females, BPH/5 adult male mice have similar body weights, daily food intake, and circulating leptin levels as compared to age-matched control mice (n=5-30; p>0.05). However, as seen in adult BPH/5 females, adult BPH/5 males have increased subcutaneous white adipose tissue (WAT) (BPH/5: 294 vs C57:133 mg; n=5-19; p<0.05) and peri-renal WAT mass (BPH/5: 188 vs C57:59 mg; n=11-22; p<0.05). BPH/5 males demonstrated cardiomegaly (190.2 mg; n=22; p<0.05) as compared to age-matched C57 adult males (168.4 mg; n=8) and on histological evaluation, evidence for cardiomyopathy was present. To investigate the BPH/5 male adipose tissue milieu, real time PCR was used to determine the inflammatory cytokine mRNA expression. Adult BPH5 male showed an increase in tumor necrosis factor alpha (TNFa) relative mRNA in the peri-renal WAT (6-fold; n=3-4; p<0.05). In subcutaneous WAT, there was a significant increase in prostaglandin synthase 2 (Ptgs-2) mRNA expression (6.5-fold; n=3; p<0.05). Pair-feeding BPH/5 dams beginning at day e0.5 and continuing through the first 9 days of pregnancy significantly decreased peri-renal WAT mass and TNFa expression (4.5-fold; n=3-6; p<0.05) as well as decreased subcutaneous WAT mass and Ptgs-2 expression compared to ad libitum fed dams’ BPH5 male offspring (3-fold; n=3-5; p<0.05). In conclusion, we believe that reduction in the maternal obesogenic environment may play an important role in BPH/5 offspring pregnancy outcomes in a sex-dependent manner. Thus, it is possible that fetal programming from an adverse maternal environment in this model could promote a pro-inflammatory response in the WAT, which may promote the development of cardiovascular disease in this mouse model. Future investigations are necessary to understand all the differences observed in BPH/5 offspring into adulthood as well as the transgenerational impact of attenuated maternal obesity in pregnancy.