Intestinal Triacylglycerol Metabolism and Energy Balance

描述（申请人提供）：肠道在脂质代谢和能量平衡中起着关键作用。它是膳食营养的入口，是含载脂蛋白b乳糜微粒的来源，也是向其他组织发出当前营养状况信号以维持体内平衡和促进代谢效率的内分泌器官。然而，参与这些过程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全身脂质代谢和能量平衡。本提案的总体目标是阐明酰基辅酶a：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的小鼠（MGAT2 -/-小鼠）对高脂肪喂养引起的肥胖和相关代谢紊乱表现出显著的抵抗力。与肠道在调节食物摄入和营养吸收方面的既定作用相反，Mgat2-/-小鼠的表型表明，肠道在调节能量消耗方面的作用以前未被认识到。在已知的MGAT酶中，MGAT2在人和小鼠肠道中高度表达。MGAT活性最为人所知的是它在膳食脂肪吸收中的作用，因为它催化三酰基甘油的再合成，这是乳糜微粒形成的必要步骤，乳糜微粒将膳食脂肪输送到周围组织。尽管消耗和吸收正常数量的脂肪，Mgat2-/-小鼠在高脂肪饮食中不会过度增加体重。然而，与对照组相比，这些老鼠消耗的能量要多得多。随着膳食脂肪的增加，能量消耗的差异也会增加。尽管Mgat2-/-小鼠吸收了正常数量的脂肪，但更多的膳食脂肪是从远端肠吸收的，从而延缓了膳食脂肪进入循环系统的时间。此外，他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。这两种肠道激素都会影响能量平衡。因此，我们假设MGAT2协调肠细胞中脂质的摄取和加工以形成乳糜微粒，并调节肠内分泌细胞中GIP和GLP1的分泌。因此，肠道MGAT2引导膳食脂肪的储存，以有效地吸收这种高热量的营养物质。为了验证我们的假设，在Aim 1中，我们将阐明MGAT2在肠道脂质代谢、乳糜微粒形成和肠道激素释放中的作用。在目标2中，我们将确定缺乏MGAT2对膳食脂肪分布的功能后果。在Aim 3中，我们将使用仅在肠道中表达MGAT2的小鼠和以相同的肠道特异性方式缺乏MGAT2的小鼠来评估肠道MGAT2对全身能量平衡的总体影响。通过完成这些目标，我们将推进我们对肠道脂质代谢如何调节全身能量平衡的理解，这将是很重要的，因为它将为理解脂肪同化建立一个新的范例，脂肪同化是一个基本的生理过程，在瘦时期对生存至关重要，但可能导致身体脂肪过剩。

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.