BBA Molecular Basis of Disease (BBA Dis), just accepted for publication our paper entitled “Site-specific effects of apolipoprotein E expression on diet-induced obesity and white adipose tissue metabolic activation”. The paper shows that brain APOE exerts a dominant inhibitory effect on white adipose tissue (WAT) mitochondrial metabolic activation that is independent of its ability to promote postprandial lipid deposition to tissues, including liver and WAT.

There is a wide perception among broader scientific community that Apoe promotes obesity via direct lipid delivery to adipose tissue in the periphery [1]. This is based on the knowledge that lipoprotein-bound Apoe is a natural ligand for Ldlr and Lrp1 [2-4].

However, Ldlr has only a minor, if any, contribution to diet-induced obesity [5,6]. Similarly, despite reports suggesting that adipose tissue Lrp1 may be implicated in diet-induced obesity [7], more recent work [8,9] showed that in the aP2-cre mouse, significant Cre activity is also found in ganglia of the peripheral nervous system (PNS), in adrenal medulla and in neurons throughout the central nervous system (CNS), proving that the aP2-cre mouse should no longer be used as a tool for adipose-tissue specific inactivation of genes [8,9]. In light of this new information, the obesity resistant phenotype of floxed-lrp1 mice crossed with aP2-cre mice could also due to Lrp1 inactivation in PNS and CNS and not in adipose tissue, as originally suggested [7].

In September 2012, I assigned Ms. Aikaterini Hatziri, a junior Ph.D student at the time to the task of investigating brain vs. peripheral effects of APOE in diet-induced obesity. In the course of her studies, other members of the lab also offered their expertise.

Today, BBA Molecular Basis of Disease (IF=5.6) accepted for publication Aikaterini’s work entitled “Site-specific effects of apolipoprotein E expression on diet-induced obesity and white adipose tissue metabolic activation”. In this new paper we show that:

a) the role of APOE in diet-induced obesity is independent of direct post-prandial lipid delivery to white adipose tissue (WAT).

b) APOE shows a bimodal relation with visceral WAT mitochondrial metabolic activation that is highly dependent on its site of expression (brain vs.periphery).

c) Peripherally expressed APOE is associated with a notable shift of substrate oxidation towards non-shivering thermogenesis in visceral WAT mitochondria, leading to resistance to obesity.

d) Brain APOE-mediated inhibition is dominant over peripheral APOE-mediated simulation of WAT mitochondrial metabolic activity.

I would like to thank Aikaterini and all my colleagues in the lab for their contribution to this piece of work which I consider a great advancement to the current state of the art in the field.

The paper is available at the Journal's website at https://authors.elsevier.com/a/1W5Hm3IQ~pyr7d.

The work was funded by the action «Excellence I» grant #248 of the Operational Program "Education and Lifelong Learning" (Action’s Beneficiary: Hellenic General Secretariat for Research and Technology), that was co-financed by the European Social Fund (ESF) and the Hellenic State.

References
[1] Hofmann SM, Perez-Tilve D, Greer TM, Coburn BA, Grant E, Basford JE et al.. Defective lipid delivery modulates glucose tolerance and metabolic response to diet in apolipoprotein E-deficient mice. Diabetes 2008;57:5-12.
[2] Kypreos KE, Teusink B, Van Dijk KW, Havekes LM, Zannis VI. Analysis of the structure and function relationship of the human apolipoprotein E in vivo, using adenovirus-mediated gene transfer. FASEB J 2001;15:1598-600.
[3] Yamamoto T, Choi HW, Ryan RO. Apolipoprotein E isoform-specific binding to the low-density lipoprotein receptor. Anal Biochem 2008;372:222-6.
[4] Ruiz J, Kouiavskaia D, Migliorini M, Robinson S, Saenko EL, Gorlatova N et al.. The apoE isoform binding properties of the VLDL receptor reveal marked differences from LRP and the LDL receptor. J Lipid Res 2005;46:1721-31.
[5] Karagiannides I, Abdou R, Tzortzopoulou A, Voshol PJ, Kypreos KE. Apolipoprotein E predisposes to obesity and related metabolic dysfunctions in mice. FEBS J 2008;275:4796-809.
[6] Constantinou C, Mpatsoulis D, Natsos A, Petropoulou PI, Zvintzou E, Traish AM et al.. The low density lipoprotein receptor modulates the effects of hypogonadism on diet-induced obesity and related metabolic perturbations. J Lipid Res 2014;55:1434-47.
[7] Hofmann SM, Zhou L, Perez-Tilve D, Greer T, Grant E, Wancata L et al.. Adipocyte LDL receptor-related protein-1 expression modulates postprandial lipid transport and glucose homeostasis in mice. J Clin Invest 2007;117:3271-82.
[8] Martens K, Bottelbergs A, Baes M. Ectopic recombination in the central and peripheral nervous system by aP2/FABP4-Cre mice: implications for metabolism research. FEBS Lett 2010;584:1054-8.
[9] Jeffery E, Berry R, Church CD, Yu S, Shook BA, Horsley V et al.. Characterization of Cre recombinase models for the study of adipose tissue. Adipocyte 2014;3:206-11.