Metabolic Basis of Disease

项目总结

Project Summary The majority of adults in the United States are overweight and/or obese. One in three adults have hypertension. The genesis of this cardiometabolic epidemic likely begins with in utero development. Adverse pregnancy outcomes, such as preeclampsia (PE), greatly increase mother and offspring risk of cardiometabolic diseases. PE is defined as maternal hypertension and multi-organ dysfunction during the second half of pregnancy. Because the signs resolve after delivery of the fetus and placenta, an abnormal fetoplacental unit is regarded as the cause of the maternal syndrome. Offspring born to PE mothers demonstrate co-morbidities, including preterm birth and fetal growth restriction (FGR), which contributes to the cardiovascular disease and obesity lifecycle. Women that begin pregnancy obese are 3 times more likely to develop PE. The precise mechanism of this is unknown and the long-term effects on offspring are unclear. To study PE, we utilize the obese female BPH/5 mice spontaneously exhibit late-gestational hypertension, fetal demise, FGR, and excessive gestational weight gain, similar to PE in women. Our overarching hypothesis is that maternal weight loss in early pregnancy can alter genetic programming and attenuate risk for adult onset cardiometabolic disease in female offspring. Adult female BPH5 have accelerated catch up growth and obesity with leptin resistance, increased blood pressure, and altered estrogen signaling before pregnancy compared to age-matched lean normotensive control mice. These cardiometabolic risk factors are not mirrored in BPH/5 males. Pregnant female BPH/5 develop excessive gestational weight gain, hypertension in the second half of pregnancy (i.e. superimposed PE), and other new onset pregnancy co-morbidities, including fatty liver. Our aims are designed to test BPH/5 dam pair-feeding beginning at conception to improve female offspring cardiometabolic phenotypic risk factors. Preliminary data supports our approach that reversal of BPH/5 maternal obesity via weight loss in the first half of gestation leads to attenuation of fetal demise and FGR in this model. Our ongoing COBRE studies are addressing the maternal syndrome of PE after maternal weight loss on placental development in BPH/5 mice and this IDeA supplement proposes to examine sex steroid hormones in female and male BPH/5 offspring as well as genetic contributors of cardiometabolic disease risk, including X-linked genes. We will use the gold standard liquid chromatography mass spectrometry for measuring sex steroid hormones as BPH/5 mice age and novel whole genome bisulfite sequencing on the X chromosome to reveal novel genetic perturbations that could contribute to the sexual dimorphism of cardiometabolic disease risk seen in BPH/5 females. Furthermore, we will investigate the epigenetic and in utero programming of maternal weight loss on these markers of cardiovascular disease. The findings of this proposal are necessary to understand the effects of PE on offspring into adulthood and their response to improvement of maternal obesity in a sex dependent manner.