Center of Research in Obesity and Cardiovascular Disease Project 2

Obesity increases the risk of developing vascular disorders, including both cardiovascular disease (CVD) and dementia. Another risk factor that has been associated with both CVD and cognitive impairments, is apolipoprotein E (apoE). There are three major isoforms of apoE (E): E2, E3, and E4. Compared to E3, the E4 isoform is associated with a 2-15 fold increased risk of developing Alzheimer’s disease (AD), while the E2 isoform is protective. Paradoxically, mice and humans with E4 have increased risks for these disorders despite having reduced adiposity, while those with E2 are protected despite increased adiposity. Our preliminary data show that mice expressing human E4 gain less weight compared to those with E2 or E3, and suggest that this reduction in adipose tissue mass is driven by a global shift in metabolism whereby E4 mice show a preference for lipids vs carbohydrates as a fuel source. Because the brain relies primarily on glucose as an energy source, we hypothesize that E4 contributes to cognitive impairment through a metabolic abnormality in which a preference toward fatty acid oxidation results in an inherent inefficiency to utilize glucose. In Aim 1, we will measure substrate uptake and utilization in the brain and heart of mice expressing human apoE. The uptake and oxidation of glucose, ketone bodies, and fatty acids will be measured in vivo i) using radiolabeled tracers during metabolic studies and ii) by leveraging the one-of-akind facilities available at UK in regards to stable isotope resolved metabolomics (SIRM). Additionally, the cellular contributions to substrate uptake and utilization will be measured in vitro using a novel live cell scintillation proximity assay, which measures in parallel both uptake and oxidation via CO2 trapping. In Aim 2, we will translate findings by measuring substrate preferences using indirect calorimetry (IC) in E2, E3 and E4-expressing individuals at rest, and during a cognitive challenge. Together, our early findings suggest that obesity, apoE, and cognition may be linked by a unifying biological mechanism related to energy substrate preference. The current proposal, aimed at uncovering the precise pathways underlying this phenomenon may provide novel biomarkers to predict latent disease, and new molecular targets for the prevention or treatment of these disorders.