The high levels of saturated fat in Western diets contribute to the risk for obesity, diabetes and cardiovascular disease. Consumption of a fat-rich mean triggers a surge in circulating triglyceride TG levels as well as an inflammatory response that last several hours. As a result, we may spend a majority of our waking hours in a postprandial state. Non-fasting/postprandial TG levels are an independent predictor for cardiovascular disease. Studies in humans of multiple ethnic groups, as well as in the mouse, indicate that biological sex is a key determinant of postprandial hyperlipidemia, with males experiencing higher postprandial TG levels and inflammatory response. Knowledge gaps remain in our understanding of the physiological and molecular processes that differ between males and females to influence postprandial lipid handling and inflammation. Furthermore, the components of biological sex (which include ovarian and testicular hormones as well as genetic sex determinants, the XX and XY sex chromosomes) have not been systematically investigated with respect to postprandial metabolism. Our preliminary studies indicate that a lipid meal leads to substantially higher and more persistent circulating TG levels in males compared to females regardless of time of meal administration (i.e., during a typical fasting or feeding period) or presence of gut microbiota (the sex difference persists in gnotobiotic mice). Male mice also experience an enhanced postprandial inflammatory response, characterized by increased circulating monocyte number and inflammatory gene expression in bone marrow cells. Preliminary mechanistic studies indicate that rates of postprandial lipoprotein appearance in the circulation are similar in males and females, but that lipid composition and lipolysis differ. Our studies in the Four Core Genotypes mouse model reveal that the sex difference in postprandial hypertriglyceridemia is associated with gonadal sex (levels correlate with presence of ovaries vs. testes), whereas postprandial LPS levels are associated with sex chromosomes (presence of XX vs. XY). We propose to identify physiological and sex-related mechanisms that drive differences in postprandial lipid metabolism between males and females. Aim 1: Identify the metabolic processes and bioactive lipid components that promote male-biased postprandial hypertriglyceridemia and inflammation. We will perform in vivo and ex vivo studies in male and female mice to identify the mechanisms that lead to sex-biases in postprandial lipid composition, lipolysis, and inflammatory activation. Aim 2: Elucidate the control of postprandial lipid metabolism and inflammation by gonadal sex and chromosomal sex. Our studies in Four Core Genotypes mice revealed that distinct sex components influence postprandial lipid levels and inflammation. We will test the hypotheses that estradiol and/or testosterone regulate postprandial TG levels (using gonadectomized mice and hormone replacement), whereas ...