Metabolic shifts toward fatty-acid usage and increased thermogenesis are associated with impaired adipogenesis in mice expressing human APOE4

J. M. Arbones-Mainar, L. A. Johnson, E. Torres-Perez, A. E. Garcia, S. Perez-Diaz, Jacob Raber, N. Maeda

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: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.Objective: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metabolic shift toward increased lipid oxidation.Methods:We employed humanized mice in which the Apoe gene has been replaced by the human APOE*3 or APOE*4 allele to produce human APOE3 or APOE4 proteins and characterized several mechanisms of fatty-acid oxidation, lipid storage,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.Results: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.Conclusion: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.International Journal of Obesity advance online publication, 7 June 2016; doi:10.1038/ijo.2016.93.

Original languageEnglish (US)
JournalInternational Journal of Obesity
DOIs
StateAccepted/In press - Jun 7 2016

Fingerprint

Adipogenesis
Thermogenesis
Apolipoproteins E
Fatty Acids
Lipids
Protein Isoforms
Postprandial Period
Apolipoprotein E3
Apolipoprotein E4
Brown Adipose Tissue
Body Temperature
Lipid Metabolism
Population
Genes
Weight Gain
Insulin Resistance
Publications
Obesity
Alleles
Body Weight

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Nutrition and Dietetics
  • Endocrinology, Diabetes and Metabolism

Cite this

Metabolic shifts toward fatty-acid usage and increased thermogenesis are associated with impaired adipogenesis in mice expressing human APOE4. / Arbones-Mainar, J. M.; Johnson, L. A.; Torres-Perez, E.; Garcia, A. E.; Perez-Diaz, S.; Raber, Jacob; Maeda, N.

In: International Journal of Obesity, 07.06.2016.

Research output: Contribution to journalArticle

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abstract = "Background: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.Objective: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.Methods: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.Results: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.Conclusion: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.International Journal of Obesity advance online publication, 7 June 2016; doi:10.1038/ijo.2016.93.",
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AU - Arbones-Mainar, J. M.

AU - Johnson, L. A.

AU - Torres-Perez, E.

AU - Garcia, A. E.

AU - Perez-Diaz, S.

AU - Raber, Jacob

AU - Maeda, N.

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