Intestinal Triacylglycerol Metabolism and Energy Balance

肠道三酰甘油代谢和能量平衡

• 批准号: 8824927
• 负责人: Chi- Liang Eric Yen
• 金额: $ 32.3万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824927
• 关键词: 2-acylglycerol O-acyltransferase; Acyl Coenzyme A; Address; Affect; Apolipoproteins B; Assimilations; Blood Circulation; Body fat; Chylomicrons; Diet; Dietary Fats; Distal; Duodenum; Eating; Endocrine Glands; Energy Metabolism; Enterocytes; Enteroendocrine Cell; Enzymes; Epidemic; Essential Fatty Acids; Fatty Acids; Fatty acid glycerol esters; Gastric Inhibitory Polypeptide; Genetic Models; Glucagon; Goals; Health; Homeostasis; Hormones; Human; Infusion procedures; Insulin Resistance; Intestines; Isotopes; Knowledge; Lead; Lipids; Lipoproteins; Lymph; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolism; Molecular; Mus; Nutrient; Nutritional status; Obesity; Peripheral; Phenotype; Physiological Processes; Play; Process; Research; Resistance; Role; Signal Transduction; Source; Testing; Time; Tissues; Tracer; Triglycerides; Universities; Vitamins; Weight Gain; Work; absorption; body system; combat; detection of nutrient; energy balance; feeding; improved; insight; lipid metabolism; novel; particle; response; therapeutic target; therapy development; uptake

DESCRIPTION (provided by applicant): The intestine plays a pivotal role in lipid metabolism and energy balance. It is the portal for dietary nutrients, the source of apolipoprotein B-containing chylomicra, and an endocrine organ that signals current nutritional status to other tissues to maintain homeostasis and promote metabolic efficiency. However, many molecular mechanisms involved in these processes remain elusive. The long-term goal of our research is to understand how intestinal lipid processing regulates systemic lipid metabolism and energy balance. The overall objective of this proposal is to elucidate the mechanism(s) by which acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) regulates whole body energy balance. Mice deficient in MGAT2 (Mgat2-/- mice) display a remarkable resistance to obesity and related metabolic disorders induced by high-fat feeding. In contrast to the well- established role of the intestine in regulating food intake and nutrient assimilation, the phenotype of Mgat2-/- mice suggests a previously unrecognized role of the intestine in modulating energy expenditure. Among known MGAT enzymes, MGAT2 is highly expressed in the intestine of human and mouse. MGAT activity is best known for its role in the absorption of dietary fat, because it catalyzes triacylglycerol re-synthesis, a required step for the formation of chylomicra, which deliver dietary fat to peripheral tissues. Despite consuming and absorbing normal amounts of fat, Mgat2-/- mice are protected from excessive weight gain on a high-fat diet. Compared to their control littermates, however, these mice expend significantly more energy. The difference in energy expenditure increases, as dietary fat increases. Although Mgat2-/- mice absorb normal quantities of fat, more of the dietary fat is absorbed from the distal intestine, thereby delaying the entry of dietary fat into the circulation. In addition, their postprandial levels of glucose-dependent insulinotropic peptide (GIP) are lower, whereas glucagon-like peptide1 (GLP1) levels are higher than in controls. Both gut hormones can affect energy balance. Thus, we hypothesize that MGAT2 coordinates the uptake and processing of lipid for chylomicron formation in enterocytes and modulates the secretion of GIP and GLP1 from enteroendocrine cells. As such, intestinal MGAT2 directs the delivery of dietary fat toward storage for efficient assimilation of this calorie-dense nutrient. To test our hypothesis, in Aim 1, we will elucidate the role of MGAT2 in intestinal lipid metabolism, chylomicron formation, and gut hormone release. In Aim 2, we will determine the functional consequences of lacking MGAT2 on the distribution of dietary fat. In Aim 3, we will assess the overall impact of intestinal MGAT2 on systemic energy balance using mice that express MGAT2 only in the intestine and mice that lack MGAT2 in the same intestine-specific manner. By completing these aims, we will advance our understanding of how intestinal lipid metabolism modulates systemic energy balance, which would be important, because it would build a new paradigm for understanding fat assimilation, a fundamental physiological process that is crucial for survival during lean times but may lead to excessive body fat in periods of abundance.

描述（由申请人提供）：肠道在脂质代谢和能量平衡中起关键作用。它是饮食营养素的门户，是载脂蛋白B的乳糖症的来源，也是内分泌器官，它向其他组织发出了当前营养状况的信号，以维持稳态并促进代谢效率。但是，这些过程中涉及的许多分子机制仍然难以捉摸。我们研究的长期目标是了解肠道脂质加工如何调节系统性脂质代谢和能量平衡。该提案的总体目的是阐明酰基COA：单酰基甘油酰基转移酶-2（MGAT2）调节全身能量平衡的机制。缺乏MGAT2（MGAT2 - / - 小鼠）的小鼠对高脂喂养引起的肥胖症和相关代谢性疾病表现出显着的抗药性。与肠道在调节食物摄入量和营养同化方面的良好作用相反，MGAT2 - / - 小鼠的表型表明，肠道中肠道中先前未识别的作用在调节能量消耗中的作用。在已知的MGAT酶中，MGAT2在人和小鼠的肠中高度表达。 MGAT活性以其在饮食脂肪的吸收中的作用而闻名，因为它催化了三酰基甘油再生合成，这是形成乳糜微粒的必需步骤，乳糜微粒为外围组织提供饮食脂肪。尽管消耗并吸收了正常量的脂肪，但MGAT2 - / - 小鼠仍受到高脂饮食的过度体重增加。但是，与他们的对照同窝仔相比，这些小鼠花费了更多的能量。随着饮食脂肪的增加，能量消耗的差异增加。尽管MGAT2 - / - 小鼠吸收了正常的脂肪，但更多的饮食脂肪会从远端肠中吸收，从而延迟了饮食脂肪进入循环。此外，它们的餐后葡萄糖依赖性胰岛素肽（GIP）水平较低，而胰高血糖素样肽1（GLP1）水平高于对照组。两种肠道激素都会影响能量平衡。因此，我们假设MGAT2协调脂质中脂质体形成脂质的摄取和加工，并调节肠内分泌细胞中GIP和GLP1的分泌。因此，肠道MGAT2将饮食脂肪的递送用于储存，以有效地吸收这种卡路里密集的营养素。为了检验我们的假设，在AIM 1中，我们将阐明MGAT2在肠道脂质代谢，乳糜微粒形成和肠激素释放中的作用。在AIM 2中，我们将确定缺乏MGAT2对饮食脂肪分布的功能后果。在AIM 3中，我们将使用仅在以相同肠特异性方式中缺乏MGAT2的小鼠中表达MGAT2的小鼠，评估肠道MGAT2对全身能量平衡的总体影响。通过完成这些目标，我们将提高人们对肠道脂质代谢如何调节系统能量平衡的理解，这很重要，因为它将建立一个新的范式来理解脂肪同化，这是一种基本的生理过程，这对于瘦时期的生存至关重要，但可能会导致多余的体内造成多余的体内造成过多的体内。