Ketogenesis in humans: Modulation by diet, exercise and ApoE

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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.