Medium Chain Triglycerides and Ketogenesis

中链甘油三酯和生酮

• 批准号: RGPIN-2020-05207
• 负责人: AlBatran, Rami
• 金额: $ 1.75万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=762029
• 关键词: Medium; Chain; Triglycerides; Ketogenesis

Background: Medium fatty acids chain occur naturally as medium chain triglycerides (MCT) and can be found in coconut and palm oils. MCT have different forms and can be purchased over the counter as a dietary supplement (MCT oil). Unlike other fatty acid, MCT provide immediate energy because they are able to cross the double mitochondrial membrane very rapidly, and this results in the production of ketone bodies (KB). Of interest, many studies have shown that MCT supplements rise circulating KB and enhance athletic performance. However, the biological actions of MCT, and the mechanisms by which MCT may enhance ketone body production (Ketogenesis) have been relatively understudied. Hence, the major aims of this proposal are to elucidate the mechanisms by which MCT supplement increases ketogenesis in liver, and subsequently this will enhance liver mitochondrial function. Hypothesis: We hypothesize that MCT supplement increases circulation KB by augmenting the fate committing ketogenic enzyme mitochondrial 3-hydroxymethylglutaryl-CoA synthase (HMGCS2), as a result this will improve hepatic mitochondrial function. Methodology: We will utilize a number of cell culture and animal approaches to reveal how MCT supplement augment KB production rates in the liver. This includes culturing and treating liver cell line (HepG2) with different forms and concentrations of MCT, and assessing the ketogenesis enzymes and hepatic mitochondrial function. Furthermore, we will subject mice to MCT-rich diet for 12 weeks to determine whether MCT treatment increases circulating KB, enhances ketogenic pathway (e.g. HMGCS2) and hepatic mitochondrial function via mRNA/protein expression profiling of liver extracts. Moreover, energy expenditure and energy substrate preference will be determined in mice subjected to MCT-rich diet via indirect calorimetry measurements. Aims: This research proposal will encompass 2 specific aims; (1) To determine whether the ketogenic enzyme (HMGCS2) is augmented in the liver following treatment with MCT, and (2) to assess whether MCT treatment increases hepatic mitochondrial function. In aim 1, we will treat cultured HepG2 with different forms and concentrations of MCT, and assess mRNA/protein expression profile of ketogenic metabolic pathway. Furthermore, we will measure circulating KB in mice subjected to MCT-rich diet and assess their whole body O2 consumption rates and respiratory exchange ratio via indirect calorimetry. In aim 2, we will assess a number of key factors involved in mitochondrial function. Impact: Our findings will yield insight into the mechanism by which MCT supplement enhances ketone body production rates and hepatic mitochondrial function. Moreover, the results of this research program also provide significant insights into what "claims" should be allowed for manufacturers who market MCT as an over-the-counter nutraceutical dietary supplement to augment KB.

背景：中链脂肪酸作为中链甘油三酯（MCT）天然存在，可在椰子油和棕榈油中发现。MCT有不同的形式，可以在柜台上购买作为膳食补充剂（MCT油）。与其他脂肪酸不同，MCT提供即时能量，因为它们能够非常迅速地穿过双线粒体膜，这导致酮体（KB）的产生。有趣的是，许多研究表明，MCT补充剂增加循环KB并提高运动表现。然而，MCT的生物学作用以及MCT可能增强酮体生成（生酮）的机制相对研究不足。因此，该提案的主要目的是阐明MCT补充增加肝脏酮生成的机制，随后这将增强肝脏线粒体功能。假设：我们假设MCT补充剂通过增加生酮酶线粒体3-羟甲基戊二酰-CoA合酶（HMGCS 2）的命运而增加循环KB，因此这将改善肝线粒体功能。方法学：我们将利用许多细胞培养和动物方法来揭示MCT补充剂如何增加肝脏中KB的产生率。这包括用不同形式和浓度的MCT培养和处理肝细胞系（HepG 2），并评估生酮酶和肝线粒体功能。此外，我们将使小鼠接受富含MCT的饮食12周，以通过肝脏提取物的mRNA/蛋白质表达谱确定MCT处理是否增加循环KB、增强生酮途径（例如HMGCS 2）和肝脏线粒体功能。此外，将通过间接量热法测量，在接受富含MCT饲料的小鼠中确定能量消耗和能量底物偏好。目的：本研究提案将包括2个特定目的：（1）确定MCT治疗后肝脏中的生酮酶（HMGCS 2）是否增加，以及（2）评估MCT治疗是否增加肝线粒体功能。在目的1中，我们将用不同形式和浓度的MCT处理培养的HepG 2，并评估生酮代谢途径的mRNA/蛋白质表达谱。此外，我们将测量接受富含MCT饲料的小鼠的循环KB，并通过间接热量测定法评估其全身O2消耗率和呼吸交换率。在目标2中，我们将评估参与线粒体功能的一些关键因素。影响：我们的研究结果将深入了解MCT补充剂增强酮体生成速率和肝线粒体功能的机制。此外，这项研究计划的结果也提供了重要的见解，什么“索赔”应该允许制造商谁市场的MCT作为一个非处方营养膳食补充剂，以增加KB。