Maternal obesity and cardiometabolic health in the offspring

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Obesity is a global health problem, leading to increased risk for cardiovascular disease, diabetes, and related complications. Additionally, the offspring of obese and overweight women are more likely than those born to normal-weight women to be obese at one year of age; to have metabolic syndrome, hypertension, and liver disease as young children; and to have cardiovascular disease as adults. The mechanisms of maternal programming of cardiac impairment in the offspring are unclear, preventing development of strategies to prevent them. We have developed a mouse model in which maternal high fat/high sucrose (HF/HS) diet-induced obesity leads to cardiac abnormalities in the offspring. Specifically, despite eating a standard diet after weaning, adult female F1 offspring of female mice (F0) fed a HF/HS diet developed significantly impaired left ventricular function as defined by decreased fractional shortening and increased left ventricular inner diameter. Our objectives here are to determine the extent to which they are inherited transgenerationally and the mechanism by which these effects occur. Our rationale is if we can determine the mechanism responsible for this maternal programming of cardiac impairment, we may be able to develop therapeutic measures to prevent this debilitating mitochondrial dysfunction. We hypothesize that this mitochondrial phenotype leading to the perturbation of cardiac function is transgenerational since it is transmitted by the oocyte. We anticipate that this phenomenon is due to epigenetic changes to either the nuclear or mitochondrial DNA (mtDNA). We also hypothesize that intra-oocyte ROS accumulation and/or lipid accumulation are responsible for the epigenetic transmission and are the direct result of maternal HF/HS diet. The three aims are designed to test these hypotheses. The results of these studies will provide a clear mechanism to explain the transmission, which will lead to new therapeutic targets. It is our goal that this work will result in novel preventative measures and potentially pharmacological products to improve the health of the next generation.