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).

西方饮食中的高含量饱和脂肪会增加肥胖、糖尿病和心血管疾病的风险 疾病。食用富含脂肪的食物会引发循环甘油三酯 TG 水平的激增以及 持续数小时的炎症反应。因此，我们醒着的大部分时间可能都在 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 餐后高脂血症的决定因素，男性餐后TG水平较高 炎症反应。我们对生理和分子的理解仍然存在知识差距 男性和女性之间影响餐后脂质处理和炎症的过程不同。 此外，生物性别的组成部分（包括卵巢和睾丸激素以及遗传性激素） 性别决定因素（XX 和 XY 性染色体）尚未得到系统研究 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 无论进餐时间如何（即， 在典型的禁食或喂养期间）或肠道微生物群的存在（性别差异在无菌菌中持续存在） 老鼠）。雄性小鼠的餐后炎症反应也增强，其特征是 骨髓细胞中循环单核细胞数量和炎症基因表达。初步机制 研究表明，餐后脂蛋白在循环中的出现率在男性和女性中相似。 女性，但脂质成分和脂肪分解不同。我们对四种核心基因型小鼠模型的研究 揭示餐后高甘油三酯血症的性别差异与性腺性别相关（水平与 卵巢与睾丸的存在），而餐后 LPS 水平与性染色体相关 （存在 XX 与 XY）。我们建议确定导致差异的生理和性别相关机制 男性和女性的餐后脂质代谢。目标 1：识别代谢过程并 促进男性餐后高甘油三酯血症的生物活性脂质成分 炎。我们将对雄性和雌性小鼠进行体内和离体研究，以确定其机制 导致餐后脂质成分、脂肪分解和炎症激活的性别偏差。目标 2：阐明 性腺性别和染色体性别对餐后脂质代谢和炎症的控制。 我们对四种核心基因型小鼠的研究表明，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（使用去性腺切除和激素替代），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*小鼠模型来比较 具有 XX、XY、XO 和 XXY 染色体互补体的动物）。