Ketogenesis in humans: Modulation by diet, exercise and ApoE

背景***研究健康成人生酮的代谢生理学是我DG项目的一个主要主题。酮类生理仍然知之甚少，但它们在整个生命周期中是葡萄糖必不可少的补充脑燃料，可以提供成人大脑能量需求的70%。******进展***在过去的5年里，我们在几个方面取得了进展，有助于更好地理解人类和大鼠的酮生和酮代谢。***目的***更好地表征中链甘油三酯（MCT）配方、不同生酮营养素、影响胰岛素敏感性的条件和ApoE基因型如何调节健康成年人的生酮。******重点项目***配方：使用不同的乳化剂和纳米乳化剂来测试标准剂量10克MCT的生酮反应。* * * 2。生酮营养素：分别以4:0 ~ 14:0的均匀链脂肪酸口服剂量对比MCT和三庚酸的生酮效果。这些脂肪酸中最具生酮性的将与亮氨酸结合进行测试。* * * 3。生酮和血浆中链脂肪酸（MCFA）：描述口服MCT后血浆中链脂肪酸水平和半衰期与生酮的关系。* * * 4。胰岛素敏感性、健康衰老和有氧运动：健康老年人尽管胰岛素敏感性下降，但生酮正常。运动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胰岛素敏感性和生酮反应的影响。* * * 5。ApoE4基因型：评估所有参与者的ApoE基因型，并在口服10g MCT前后检测13c -三辛酸的代谢，以测量ApoE4携带者和非携带者的血浆MCFA动力学和β -氧化。******方法***我们严格筛选所有年龄段的潜在参与者，根据无医疗条件或处方药、正常代谢谱和正常认知测试结果选择健康的参与者。我们的生酮测试是基于早餐时给予测试物质后4小时的血液采样周期，与10克标准MCT进行比较。我们的设备齐全，可以分析血液代谢物和13C示踪剂。这些项目将由10-12名参与者/小组提供足够的动力。******影响***我们似乎是加拿大唯一一个研究人类生酮代谢生理学的实验室，这一过程对确保大脑不间断的燃料供应很重要，但人们对这一过程知之甚少。这个DG项目将继续训练HQP，并有助于理解某些饮食和运动习惯如何改善代谢健康和生酮反应。这个项目奠定了我的概念，即在婴儿身体脂肪中储存MCFA并将其用于生酮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. ********