Sex Differences in Postprandial Lipid Metabolism

餐后脂质代谢的性别差异

• 批准号: 10540166
• 负责人: Karen Reue
• 金额: $ 44.93万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-20 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540166
• 关键词: Animals; Appearance; Bacteria; Blood Circulation; Bone Marrow Cells; Cardiometabolic Disease; Cardiovascular Diseases; Cells; Ceramides; Chromosomes; Consumption; Country; Data; Development; Diabetes Mellitus; Diet; Eating; Endotoxemia; Endotoxins; Estradiol; Ethnic group; Fasting; Fatty Liver; Fatty acid glycerol esters; Female; Four Core Genotypes; Gene Expression; Gnotobiotic; Goals; Gonadal Hormones; High Fat Diet; Hormones; Hour; Human; Hyperlipidemia; Hypertriglyceridemia; Individual; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Intake; Intervention; Knowledge; Lead; Lipids; Lipolysis; Lipopolysaccharides; Lipoproteins; Long-Term Effects; Measures; Metabolic Diseases; Metabolism; Modeling; Modernization; Molecular; Mus; Oral; Ovarian; Ovarian hormone; Ovary; Physiological; Ploidies; Preventive; Process; Production; Risk Factors; Role; Sex Bias; Sex Chromosomes; Sex Differences; Societies; Sphingomyelins; Testicular Hormones; Testing; Testis; Testosterone; Therapeutic; Time; Tissues; Triglycerides; Woman; X Chromosome; Y Chromosome; absorption; age group; base; biological sex; blood lipid; experience; feeding; genotypic sex; gut microbiota; in vivo; lipid metabolism; lipidomics; male; men; monocyte; mouse model; novel; obesity risk; saturated fat; sex; trait; uptake; western diet

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 the sex chromosome complement is a determinant of postprandial endotoxemia and inflammatory responses (using the XY* mouse model to compare animals with XX, XY, XO and XXY chromosome complements).

西方饮食中高水平的饱和脂肪会增加肥胖、糖尿病和心血管疾病的风险。 疾病摄入高脂肪的食物会引发循环中甘油三酯水平的激增， 持续数小时的炎症反应因此，我们可能会把大部分醒着的时间花在 餐后状态非空腹/餐后TG水平是心血管疾病的独立预测因子。 对多个种族的人类以及小鼠的研究表明，生物性别是一个关键因素， 餐后高脂血症的决定因素，男性餐后TG水平较高， 炎症反应。在我们对生理学和分子生物学的理解上， 影响餐后脂质处理和炎症的过程在男性和女性之间存在差异。 此外，生物性别的组成部分（包括卵巢和睾丸激素以及遗传因素） 性决定因素，XX和XY性染色体）尚未系统地研究 餐后代谢我们的初步研究表明，高脂膳食导致显著更高， 与女性相比男性的持续循环TG水平与进餐时间无关（即， 在典型的禁食或进食期间）或肠道微生物群的存在（性别差异在gnotobiotic 小鼠）。雄性小鼠也经历增强的餐后炎症反应，其特征在于增加的 循环单核细胞数量和骨髓细胞中的炎症基因表达。初步机理 研究表明，餐后脂蛋白在循环中的出现率在男性中相似， 女性，但脂质组成和脂解不同。我们在四个核心基因型小鼠模型中的研究 显示餐后高睾酮血症的性别差异与性腺性别有关（水平相关 卵巢与睾丸），而餐后LPS水平与性染色体相关 （XX与XY的存在）。我们建议确定驱动差异的生理和性别相关机制 在男性和女性之间的餐后脂质代谢。目的1：确定代谢过程， 促进男性偏好的餐后高脂血症的生物活性脂质成分， 炎症我们将在雄性和雌性小鼠中进行体内和体外研究，以确定其机制。 这导致餐后脂质组成、脂解和炎症激活中性别偏见。目标2：阐明 通过性腺性别和染色体性别控制餐后脂质代谢和炎症。 我们在四个核心基因型小鼠中的研究表明，不同的性别成分影响餐后脂质 水平和炎症。我们将检验雌二醇和/或睾酮调节餐后TG的假设 水平（使用性腺切除小鼠和激素替代），而性染色体补体是一个 餐后内毒素血症和炎症反应的决定因素（使用XY* 小鼠模型比较 具有XX、XY、XO和XXY染色体补体的动物）。