Final Report Summary - APOMET (Apolipoprotein E gene in the Metabolic Syndrome) Apolipoprotein E (APOE) associates with lipoproteins and mediates their clearance. In humans, the APOE gene is polymorphic and has three alleles, APOE*2, APOE*3 and APOE*4. Carrying the APOE*4 allele has been associated with an increased cardiovascular risk, predisposition to develop Alzheimer’s disease and insulin resistance. Recently, APOE*4 has also been linked with the Metabolic Syndrome (MetS), a condition closely linked to disturbances in lipid and glucose metabolism. However, the mechanisms whereby this association occurs are not clear. In this project we investigated the role of APOE in the MetS employing a multidisciplinary approach: in vivo analysis of transgenic mice coupled with epidemiological analysis of human populations. At the population level, we have identified an association between APOE2 and increased body mass index (BMI) in the Aragon Workers Health Study (AWHS) cohort, an ongoing longitudinal study targeted to study genetic determinants and life style habits that favor the appearance and progression of cardiovascular risk factors. Using this cohort we have also found a gene dose-dependent association between APOE*4 allele and increased risk for MetS and proved that this association primarily derived from the overweight subjects. Additionally, we found an unexpected role of APOE on miscarriage risk. In white women followed up for 25 years, the odds ratio for miscarriage associated with APOE*2 allele presence was increased compared with APOE*33 carriers. Interestingly, this was a race-dependent phenomenon as no associations between APOE alleles and miscarriage was observed in black women. To elucidate the molecular underpinnings of APOE-directed metabolic alterations, we tested the hypothesis that APOE4 drives a whole-body metabolic shift toward increased lipid oxidation. We employed humanized mice in which the Apoe gene has been replaced by the human APOE*3 or APOE*4 allele. We showed that APOE4 mice had a reduced respiratory quotient during the postprandial period indicating increased usage of lipids as opposed to carbohydrates as a fuel source. Furthermore, APOE4 mice showed increased body temperature, augmented cold tolerance and more metabolically active brown adipose tissue compared with APOE3 mice. These data suggest that APOE4 mice may resist weight gain via an APOE4-directed global metabolic shift toward lipid oxidation and enhanced thermogenesis, and may represent a critical first step in the development of APOE-directed therapies for a large percentage of the population affected by disorders with established links to APOE and metabolism.This grant has benefited the career of the researcher in two different manners; the researcher has been able to fulfill his long-term scientific goal of developing a better understanding of the molecular mechanisms involved in controlling energy expenditure and fat deposition. On the other hand, the researcher has launched his own research group within the Aragon Institute of Health Sciences, currently formed by 1 Masters student, 3 PhD students and 1 laboratory technician. The Integration Grant has strengthened his path to independence and it will represent a major leap toward becoming a fully independent researcher in the Translational Research field.
