Effects of Maternal Obesity on Offspring Immune System

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Project Summary/Abstract Obesity has reached epidemic proportions in the U.S, and recent studies have demonstrated that the children of obese mothers are far more likely to become obese than the children of non-obese mothers. The explanation for this association is unknown. Since obesity is associated with a widespread macrophage- dependent inflammatory state, we hypothesize that obesity-associated factors in obese mothers cross the placental barrier and adversely affect the fetal immune system. We further hypothesize that monocytes, which constitute a substantial portion of immune cells in the developing fetus, are particularly sensitive to such factors. Our preliminary data support this concept; we show that monocytes in the fetuses of diet-induced obese mice are phenotypically altered relative to the same cells in the fetuses of non-obese mice fed a normal diet. Therefore, in this proposal, in Aim 1 we will decipher the effects of maternal obesity on developing monocytes in the liver and placenta at the phenotypic, functional, epigenetic and transcriptional levels. Additionally, we will use mass cytometry in combination with our novel Scaffolds algorithm to analyze changes of monocytes and other major immune cell populations in multiple tissues and at multiple time points in the offspring of normal versus obese mice. In Aim 2, based on preliminary data showing that high-fat diet fed female mice have increased levels of cholesterol and fatty acids, which can cross the placenta, we will directly test the effects of these factors on fetal monocyte function. Upon completion of the proposed studies, we will have identified maternal factors that affect fetal monocytes and potentially other immune cells, and we will learn if their effects persist after birth.