Sex Differences in Postprandial Lipid Metabolism

餐后脂质代谢的性别差异

• 批准号: 10667618
• 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/10667618
• 关键词: Animals; Appearance; Bacteria; Bone Marrow Cells; Cardiometabolic Disease; Cardiovascular Diseases; Cells; Ceramides; Chromosomes; Circulation; Consumption; Country; Data; Development; Diabetes Mellitus; Diet; Eating; Endotoxemia; Endotoxins; Estradiol; Ethnic Population; 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; 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; Y Chromosome; absorption; age group; 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。摄入富含脂肪的平均值会触发循环中甘油三酯TG水平的激增，以及 持续数小时的炎症反应。因此，我们可能会在醒着的大部分时间里 餐后状态。非空腹/餐后甘油三酯水平是心血管疾病的独立预测因子。 在多个种族的人身上以及在老鼠身上的研究表明，生物性行为是一个关键 餐后高脂血症的决定因素，男性餐后甘油三酯水平和 炎症反应。在我们对生理学和分子生物学的理解中仍然存在着知识空白 影响餐后脂肪处理和炎症的男性和女性不同的过程。 此外，生物性行为的组成部分(包括卵巢和睾丸激素以及基因 性决定因素，XX和XY性染色体)还没有被系统地研究 餐后代谢。我们的初步研究表明，脂肪餐会导致更高和更多的 与女性相比，男性的持续循环甘油三酯水平与用餐时间无关(即， 在典型的禁食或喂食期间)或存在肠道微生物区系(性别差异持续存在于灵知菌 老鼠)。雄性小鼠也经历了增强的餐后炎症反应，其特征是 骨髓细胞外周血单核细胞数量与炎症基因表达。初步机械论 研究表明，血液循环中出现餐后脂蛋白的比率在男性和 女性，但脂质成分和脂解作用不同。我们在四种核心基因型鼠模型中的研究 显示餐后高甘油三酯血症的性别差异与性腺性别有关(水平相关 存在卵巢和睾丸)，而餐后内毒素水平与性染色体有关 (存在XX与XY)。我们建议找出驱动差异的生理和性相关机制。 在男性和女性之间的餐后脂代谢。目标1：确定代谢过程和 促进男性偏向的餐后高甘油三酯血症的生物活性脂质成分 发炎。我们将在雄性和雌性小鼠身上进行体内和体外研究，以确定其机制 这会导致餐后脂肪组成、脂肪分解和炎症激活的性别偏见。目标2：澄清 性腺性别和染色体性别对餐后脂代谢和炎症的控制。 我们对四种核心基因型鼠的研究表明，不同的性别成分会影响餐后血脂 水平和炎症。我们将检验雌激素和/或睾酮调节餐后甘油三酯的假设。 水平(使用性腺切除小鼠和激素替代)，而性染色体补体是 餐后内毒素血症和炎症反应的决定因素(使用XY*小鼠模型进行比较 具有XX、XY、XO和XXY染色体互补的动物)。