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Animal Models

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

International Journal of Obesity volume 40, pages 1574–1581 (2016)Cite this article

Subjects

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We employed humanized mice in which the Apoe gene has been replaced by the human APOE*3 or APOE*4 allele to produce human APOE3 or APOE4 proteins and characterized several mechanisms of fatty-acid oxidation, lipid storage,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.

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References

  1. Davignon J, Gregg RE, Sing CF . Apolipoprotein E polymorphism and atherosclerosis. Arterioscler Thromb Vasc Biol 1988; 8: 1–21.

    CAS  Google Scholar 

  2. Bennet AM, Di Angelantonio E, Ye Z, Wensley F, Dahlin A, Ahlbom A et al. Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA 2007; 298: 1300–1311.

    Article  CAS  Google Scholar 

  3. Dart A, Sherrard B, Simpson H . Influence of apo E phenotype on postprandial triglyceride and glucose responses in subjects with and without coronary heart disease. Atherosclerosis 1997; 130: 161–170.

    Article  CAS  Google Scholar 

  4. Elosua R, Demissie S, Cupples LA, Meigs JB, Wilson PWF, Schaefer EJ et al. Obesity modulates the association among APOE genotype, insulin, and glucose in men. Obes Res 2003; 11: 1502–1508.

    Article  CAS  Google Scholar 

  5. Torres-Perez E, Ledesma M, Garcia-Sobreviela MP, Leon-Latre M, Arbones-Mainar JM . Apolipoprotein E4 association with metabolic syndrome depends on body fatness. Atherosclerosis 2016; 245: 35–42.

    Article  CAS  Google Scholar 

  6. Talbot K, Wang H-Y, Kazi H, Han L-Y, Bakshi KP, Stucky A et al. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest 2012; 122: 1316–1338.

    Article  CAS  Google Scholar 

  7. Small GW, Mazziotta JC, Collins MT, Baxter LR, Phelps ME, Mandelkern MA et al. APolipoprotein e type 4 allele and cerebral glucose metabolism in relatives at risk for familial alzheimer disease. JAMA J Am Med Assoc 1995; 273: 942–947.

    Article  CAS  Google Scholar 

  8. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993; 261: 921–923.

    Article  CAS  Google Scholar 

  9. Chen L, Magliano DJ, Zimmet PZ . The worldwide epidemiology of type 2 diabetes mellitus-present and future perspectives. Nat Rev Endocrinol 2011; 8: 228–236.

    Article  Google Scholar 

  10. Poulos SP, Hausman DB, Hausman GJ . The development and endocrine functions of adipose tissue. Mol Cell Endocrinol 2010; 323: 20–34.

    Article  CAS  Google Scholar 

  11. Virtue S, Vidal-Puig A . Adipose tissue expandability, lipotoxicity and the metabolic syndrome—an allostatic perspective. Biochim Biophys Acta 2010; 1801: 338–349.

    Article  CAS  Google Scholar 

  12. Arbones-Mainar JM, Johnson LA, Altenburg MK, Maeda N . Differential modulation of diet-induced obesity and adipocyte functionality by human apolipoprotein E3 and E4 in mice. Int J Obes 2008; 32: 1595–1605.

    Article  CAS  Google Scholar 

  13. Arbones-Mainar JM, Johnson LA, Altenburg MK, Kim H-S, Maeda N . Impaired adipogenic response to thiazolidinediones in mice expressing human apolipoproteinE4. FASEB J 2010; 24: 3809–3818.

    Article  CAS  Google Scholar 

  14. Tejedor MT, Garcia-Sobreviela MP, Ledesma M, Arbones-Mainar JM . The Apolipoprotein E polymorphism rs7412 associates with body fatness independently of plasma lipids in middle aged men. PLoS One 2014; 9: e108605.

    Article  Google Scholar 

  15. Knouff C, Hinsdale ME, Mezdour H, Altenburg MK, Watanabe M, Quarfordt SH et al. Apo E structure determines VLDL clearance and atherosclerosis risk in mice. J Clin Invest 1999; 103: 1579–1586.

    Article  CAS  Google Scholar 

  16. Lee J, Ellis JMM, Wolfgang MJJ . Adipose fatty acid oxidation is required for thermogenesis and potentiates oxidative stress-induced inflammation. Cell Rep 2015; 10: 266–279.

    Article  CAS  Google Scholar 

  17. Canoon B, Nedergaard J . Brown adipose tissue: function and physiological significance. Physiol Rev 2004; 84: 277–359.

    Article  Google Scholar 

  18. International Diabetes Federation IDF Diabetes Atlas. International Diabetes Federation, Executive Office, 2015.

  19. Petkeviciene J, Smalinskiene A, Luksiene DI, Jureniene K, Ramazauskiene V, Klumbiene J et al. Associations between apolipoprotein E genotype, diet, body mass index, and serum lipids in Lithuanian adult population. PLoS One 2012; 7: e41525.

    Article  CAS  Google Scholar 

  20. Rodríguez-Carmona Y, Pérez-Rodríguez M, Gámez-Valdez E, López-Alavez FJ, Hernández-Armenta CI, Vega-Monter N et al. Association between Apolipoprotein E variants and obesity-related traits in Mexican school children. J Nutrigenet Nutrigenomics 2015; 7: 243–251.

    Article  Google Scholar 

  21. Volcik KA, Barkley RA, Hutchinson RG, Mosley TH, Heiss G, Sharrett AR et al. Apolipoprotein E polymorphisms predict low density lipoprotein cholesterol levels and carotid artery wall thickness but not incident coronary heart disease in 12,491 ARIC study participants. Am J Epidemiol 2006; 164: 342–348.

    Article  Google Scholar 

  22. Picard F, Géhin M, Annicotte J-S, Rocchi S, Champy M-F, O’Malley BW et al. SRC-1 and TIF2 control energy balance between white and brown adipose tissues. Cell 2002; 111: 931–941.

    Article  CAS  Google Scholar 

  23. McGarry JD, Foster DW . Regulation of hepatic fatty acid oxidation and ketone body production. Annu Rev Biochem 1980; 49: 395–420.

    Article  CAS  Google Scholar 

  24. Huebbe P, Dose J, Schloesser A, Campbell G, Glüer C-C, Gupta Y et al. Apolipoprotein E (APOE) genotype regulates body weight and fatty acid utilization—Studies in gene-targeted replacement mice. Mol Nutr Food Res 2015; 59: 334–343.

    Article  CAS  Google Scholar 

  25. Ferrannini E . The theoretical bases of indirect calorimetry: a review. Metab - Clin Exp 2016; 37: 287–301.

    Article  Google Scholar 

  26. Elia M, Livesey G . Theory and validity of indirect calorimetry during net lipid synthesis. Am J Clin Nutr 1988; 47: 591.

    Article  CAS  Google Scholar 

  27. Houstis N, Rosen ED, Lander ES . Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 2006; 440: 944–948.

    Article  CAS  Google Scholar 

  28. Jofre-Monseny L, Minihane A-M, Rimbach G . Impact of apoE genotype on oxidative stress, inflammation and disease risk. Mol Nutr Food Res 2008; 52: 131–145.

    Article  CAS  Google Scholar 

  29. Oelkrug R, Kutschke M, Meyer CW, Heldmaier G, Jastroch M . Uncoupling protein 1 decreases superoxide production in brown adipose tissue mitochondria. J Biol Chem 2010; 285: 21961–21968.

    Article  CAS  Google Scholar 

  30. Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S, Kumagai H et al. Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab 2007; 6: 55–68.

    Article  CAS  Google Scholar 

  31. Qiao L, Yoo HS, Bosco C, Lee B, Feng G-S, Schaack J et al. Adiponectin reduces thermogenesis by inhibiting brown adipose tissue activation in mice. Diabetologia 2014; 57: 1027–1036.

    Article  CAS  Google Scholar 

  32. Yamauchi T, Nio Y, Maki T, Kobayashi M, Takazawa T, Iwabu M et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med 2007; 13: 332–329.

    Article  CAS  Google Scholar 

  33. Pendse AA, Arbones-Mainar JM, Johnson LA, Altenburg MK, Maeda N . Apolipoprotein E knock-out and knock-in mice: atherosclerosis, metabolic syndrome, and beyond. J Lipid Res 2009; 50: S178–S182.

    Article  Google Scholar 

  34. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R et al. Effects of age, sex, and ethnicity on the association between apolipoprotein e genotype and alzheimer disease: a meta-analysis. JAMA 1997; 278: 1349–1356.

    Article  CAS  Google Scholar 

  35. Raber J, Huang Y, Ashford JW . ApoE genotype accounts for the vast majority of AD risk and AD pathology. Neurobiol Aging 2004; 25: 641–650.

    Article  CAS  Google Scholar 

  36. Xu W, Qiu C, Gatz M, Pedersen NL, Johansson B, Fratiglioni L . Mid- and late-life diabetes in relation to the risk of dementia: a population-based Twin study. Diabetes 2009; 58: 71–77.

    Article  CAS  Google Scholar 

  37. Peila R, Rodriguez BL, Launer LJ . Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes 2002; 51: 1256–1262.

    Article  CAS  Google Scholar 

  38. Cunnane S, Nugent S, Roy M, Courchesne-Loyer A, Croteau E, Tremblay S et al. Brain fuel metabolism, aging, and Alzheimer’s disease. Nutrition 2011; 27: 3–20.

    Article  CAS  Google Scholar 

  39. van Himbergen TM, Beiser AS, Ai M, Seshadri S, Otokozawa S, Au R et al. Biomarkers for insulin resistance and inflammation and the risk for all-cause dementia and Alzheimer disease: results from the Framingham Heart Study. Arch Neurol 2012; 69: 594–600.

    Article  Google Scholar 

Download references

Acknowledgements

JMA-M is supported by the Instituto de Salud Carlos III (Madrid, Spain) with a Miguel Servet fellowship and a specific grant (Acción Estratégica en Salud, PI14/00508). The Diputación General de Aragón (Spain) and the Marie-Curie Action APOMET from the European Commission also provide financial support to this project. We thank Professor Jose Maria Sanz for his valuable feedback and inspiring comments.

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Authors and Affiliations

  1. 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

    J M Arbones-Mainar, E Torres-Perez & S Perez-Diaz

  2. CIBER Fisiopatología Obesidad y Nutrición (CIBERObn), Instituto Salud Carlos III, Madrid, Spain

    J M Arbones-Mainar

  3. Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    J M Arbones-Mainar, L A Johnson, A E Garcia & N Maeda

  4. Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, USA

    L A Johnson & J Raber

  5. Departments of Neurology and Radiation Medicine, Division of Neuroscience, ONPRC, Oregon Health and Science University, Portland, OR, USA

    J Raber

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  1. J M Arbones-Mainar
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  2. L A Johnson
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  3. E Torres-Perez
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  6. J Raber
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  7. N Maeda
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Correspondence to J M Arbones-Mainar.

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Arbones-Mainar, J., Johnson, L., Torres-Perez, E. et al. Metabolic shifts toward fatty-acid usage and increased thermogenesis are associated with impaired adipogenesis in mice expressing human APOE4. Int J Obes 40, 1574–1581 (2016). https://doi.org/10.1038/ijo.2016.93

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