Ketogenesis in humans: Modulation by diet, exercise and ApoE

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。酮生理学仍然知之甚少，但它们是整个生命周期中葡萄糖的重要补充大脑燃料，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，有助于更好地了解人类和大鼠的酮生成和酮代谢。目的 * 更好地表征中链甘油三酯（MCT）制剂、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 *1.制剂：使用不同的乳化剂和纳米乳化剂检测标准10 g剂量MCT的生酮反应。*2。生酮营养素：检测4：0至14：0的偶链脂肪酸口服剂量与MCT和三庚酸甘油酯单独给药的生酮效应。这些脂肪酸中生酮性最强的脂肪酸将与亮氨酸联合检测。*3。生酮和血浆中链脂肪酸（MCFA）：表征MCT口服给药后血浆MCFA水平和与生酮相关的半衰期。*4。胰岛素敏感性、健康老龄化和有氧运动：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MCT引起的胰岛素敏感性和生酮的影响。*5。ApoE 4基因型：评估所有受试者的ApoE基因型，并在口服10 g MCT前后检测13 C-三辛酸甘油酯的代谢，以测量ApoE 4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，以选择那些基于没有医疗条件或处方药，正常代谢特征和正常认知测试结果的健康参与者。我们的生酮试验基于早餐时给予供试品后4小时的血样采集期，并与10 g标准MCT进行比较。我们配备齐全的血液代谢物和13 C示踪剂分析。这些项目将由10-12名参与者/组提供足够的动力。** 影响 * 我们似乎是唯一一个研究人类生酮代谢生理学的加拿大实验室，这一过程知之甚少，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。这个程序支持了我的概念，即在婴儿体脂中储存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. ********