title: Metabolic shifts toward fatty-acid usage and increased thermogenesis are associated with impaired adipogenesis in mice expressing human APOE4.
abstract: The Apolipoprotein E (APOE) gene encodes for three isoforms in the human population (APOE2, APOE3 and APOE4). Whereas the role of APOE in lipid metabolism is well characterized, the specific metabolic signatures of the APOE isoforms during metabolic disorders, remain unclear.
  
  
  
  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  We employed humanized mice in which the Apoe gene has been replaced by the human APOE*3 or APOE*4 allele to produce human APOE3 or APOE4 proteins and characterized several mechanisms of fatty-acid oxidation, lipid storage, substrate utilization and thermogenesis in those mice.
  
  
  
  We show that, whereas APOE4 mice gained less body weight and mass than their APOE3 counterparts on a Western-type diet (P<0.001), they displayed elevated insulin and homeostatic model assessment, markers of insulin resistance (P=0.004 and P=0.025, respectively). APOE4 mice also demonstrated a reduced respiratory quotient during the postprandial period (0.95±0.03 versus 1.06±0.03, P<0.001), indicating increased usage of lipids as opposed to carbohydrates as a fuel source. Finally, APOE4 mice showed increased body temperature (37.30±0.68 versus 36.9±0.58 °C, P=0.039), 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.
authors.affiliation: Adipocyte and Fat Biology Laboratory (AdipoFat), Instituto de Investigacion Sanitaria Aragon, Instituto Aragonés de Ciencias de la Salud, Unidad de Investigación Traslacional, Hospital Universitario Miguel Servet, Zaragoza, Spain.|CIBER Fisiopatología Obesidad y Nutrición (CIBERObn), Instituto Salud Carlos III, Madrid, Spain.|Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Arbones-Mainar
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Johnson
authors.affiliation: Adipocyte and Fat Biology Laboratory (AdipoFat), Instituto de Investigacion Sanitaria Aragon, Instituto Aragonés de Ciencias de la Salud, Unidad de Investigación Traslacional, Hospital Universitario Miguel Servet, Zaragoza, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Torres-Perez
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Garcia
authors.affiliation: Adipocyte and Fat Biology Laboratory (AdipoFat), Instituto de Investigacion Sanitaria Aragon, Instituto Aragonés de Ciencias de la Salud, Unidad de Investigación Traslacional, Hospital Universitario Miguel Servet, Zaragoza, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Perez-Diaz
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, USA.|Departments of Neurology and Radiation Medicine, Division of Neuroscience, ONPRC, Oregon Health and Science University, Portland, OR, USA.
authors.forename: J
authors.initials: J
authors.lastname: Raber
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: N
authors.initials: N
authors.lastname: Maeda
mesh_terms: D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism*; D050156:Adipogenesis; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D001835:Body Weight; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism*; D018014:Gene Transfer Techniques; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D022722:Thermogenesis
chemical_list: D053327:Apolipoprotein E4; D005227:Fatty Acids