Ketogenesis in humans: Modulation by diet, exercise and ApoE

背景 在健康成年人中研究酮体生成的代谢生理学是我的DG计划的一个主要主题。酮的生理学仍然知之甚少，但它们是生命周期中葡萄糖的必要补充大脑燃料，可以提供约70%的成人大脑能量需求。 进展 在过去的5年里，我们在几个方面取得了进展，这有助于更好地理解人类和大鼠体内的酮发生和酮代谢。 客观化 为了更好地描述中链甘油三酯(MCT)配方、不同的生酮营养素、影响胰岛素敏感性的条件和载脂蛋白E基因如何影响健康成年人的酮体生成。 重点项目 1.配方：使用不同的乳化剂和纳米乳化来测试酮的生成，以响应标准剂量的MCT。 2.生酮营养素：分别测试口服4：0至14：0偶数链脂肪酸与MCT和三庚烷的生酮效果。这些脂肪酸中生酮能力最强的将与亮氨酸一起进行测试。 3.酮体生成和血浆中链脂肪酸(MCFA)：测定口服MCT后血浆MCFA水平和半衰期与酮体生成的关系。 4.胰岛素敏感性、健康衰老和有氧运动：尽管胰岛素敏感性下降，但健康老年人仍有正常的酮体生成。锻炼有助于保持胰岛素敏感性。我们将在健康的年轻人、中年人和老年人中测试有氧运动对MCT反应的胰岛素敏感性和酮体生成的影响。 5.载脂蛋白E4基因分型：评估所有受试者的载脂蛋白E基因分型，并检测口服10g MCT前后13C-三辛酸的代谢，以测定载脂蛋白E4携带者和非携带者的血浆MCFA动力学和β-氧化反应。 方法 我们严格筛选所有年龄段的潜在参与者，根据没有医疗条件或处方药、代谢特征正常和认知测试结果正常的人来选择健康的人。我们的生酮测试是基于早餐服用受试物后4小时的血液采样，而标准MCT为10克。我们为血液代谢物和13C示踪剂的分析提供了全面的设备。这些项目将由10-12名参与者/小组提供足够的动力。 冲击 我们似乎是唯一一个研究人类酮体生成代谢生理学的加拿大实验室，这个过程人们知之甚少，但对确保不间断的大脑燃料供应很重要。该DG计划将继续培训HQP，并应有助于了解某些饮食和运动习惯如何改善代谢健康和生酮反应。这个项目支持了我的观点，即在婴儿体内脂肪中储存MCFA并将其用于酮生成的能力可能对人类大脑的进化做出了重大贡献。

BACKGROUND Investigating the metabolic physiology of ketogenesis in healthy adults is a major theme of my DG program. Ketone physiology is still poorly understood yet they are essential complementary brain fuels to glucose throughout the life cycle and can supply =70% of adult brain energy needs. PROGRESS Over the past 5 years, we have progressed on several fronts that contribute to a better understanding of ketogenesis and ketone metabolism in humans and in the rat. OBJECTIVE To better characterize how ketogenesis in healthy adult humans is modeulated by medium chain triglyceride (MCT) formulation, different ketogenic nutrients, conditions affecting insulin sensitivity, and ApoE genotype. KEY PROJECTS 1. Formulation: Use different emulsifiers and nanoemulsification to test ketogenesis in response to a standard 10 g dose of MCT. 2. Ketogenic nutrients: Test the ketogenic effect of oral doses of even chain fatty acids from 4:0 to 14:0 separately vs. MCT and triheptanoin. The most ketogenic of these fatty acids will be tested in combination with leucine. 3. Ketogenesis and plasma medium chain fatty acids (MCFA): Characterize plasma MCFA levels and half-life in relation to ketogenesis following an oral dose of MCT. 4. Insulin sensitivity, healthy aging and aerobic exercise: Healthy older persons have normal ketogenesis despite declining insulin sensitivity. Exercise helps maintain insulin sensitivity. We will test the effect of aerobic exercise on insulin sensitivity and ketogenesis in response to MCT in healthy young, middle-aged and older adults. 5. ApoE4 genotype: Assess ApoE genotype in all participants and test the metabolism of 13C-trioctanoin before and after a 10 g oral dose of MCT so as to measure plasma MCFA kinetics and beta-oxidation in ApoE4 carriers and non-carriers. METHODS We rigorously screen prospective participants of all ages to select those who are healthy based on absence of medical conditions or prescription drugs, normal metabolic profile and normal cognitive test results. Our ketogenic test is based on a 4 h blood sampling period after the test substance is given at breakfast with comparison to 10 g of a standard MCT. We are fully equipped for analysis of blood metabolites and 13C tracers. These projects will be sufficiently powered by 10-12 participants/group. IMPACT We seem to be the only Canadian lab studying the metabolic physiology of ketogenesis in humans, a process which is poorly understood yet important to ensure uninterrupted brain fuel supply. This DG program will continue to train HQP and should contribute towards understanding how certain dietary and exercise habits can improve metabolic health and ketogenic responsiveness. This program underlies my concept that the capacity to store MCFA in infant body fat and use them for ketogenesis probably contributed significantly to human brain evolution.