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Obligatory role of endoplasmic reticulum in brain FDG uptake

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

The endoplasmic reticulum (ER) contains hexose-6P-dehydrogenase (H6PD). This enzyme competes with glucose-6P-phosphatase for processing a variety of phosphorylated hexoses including 2DG-6P. The present study aimed to verify whether this ER glucose-processing machinery contributes to brain FDG uptake.

Methods

Effect of the H6PD inhibitor metformin on brain 18F-FDG accumulation was studied, in vivo, by microPET imaging. These data were complemented with the in vitro estimation of the lumped constant (LC). Finally, reticular accumulation of the fluorescent 2DG analogue 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2NBDG) and its response to metformin was studied by confocal microscopy in cultured neurons and astrocytes.

Results

Metformin halved brain 18F-FDG accumulation without altering whole body tracer clearance. Ex vivo, this same response faced the doubling of both glucose consumption and lactate release. The consequent fall in LC was not explained by any change in expression or activity of its theoretical determinants (GLUTs, hexokinases, glucose-6P-phosphatase), while it agreed with the drug-induced inhibition of H6PD function. In vitro, 2NBDG accumulation selectively involved the ER lumen and correlated with H6PD activity being higher in neurons than in astrocytes, despite a lower glucose consumption.

Conclusions

The activity of the reticular enzyme H6PD profoundly contributes to brain 18F-FDG uptake. These data challenge the current dogma linking 2DG/FDG uptake to the glycolytic rate and introduce a new model to explain the link between 18-FDG uptake and neuronal activity.

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Acknowledgements

The authors are indebted with Proff. Antonio De Flora, Alessandro Morelli and Alberto Pupi for the enthusiastic support and criticisms.

Funding

This study was funded by the program “Ricerca Corrente,” line “Guest-Cancer Interactions,” by Compagnia di San Paolo (project ID Prot.: 2015.AAI4110.U4917).

Author information

Authors and Affiliations

  1. Nuclear Medicine, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, Italy

    Vanessa Cossu, Cecilia Marini, Anna Maria Orengo, Matteo Bauckneht, Selene Capitanio, Nikola Yosifov, Silvia Morbelli & Gianmario Sambuceti

  2. CNR Institute of Molecular Bioimaging and Physiology (IBFM), Milan, Italy

    Cecilia Marini & Gianmario Sambuceti

  3. Cell Biology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy

    Patrizia Piccioli, Enrica Balza & Patrizia Castellani

  4. Center for Synaptic Neuroscience and Technology, Italian Institute of Technology (IIT), Genoa, Italy

    Anna Rocchi & Fabio Benfenati

  5. Department of Experimental Medicine, University of Genoa, Genoa, Italy

    Silvia Bruno & Silvia Ravera

  6. Animal Facility, IRCCS Ospedale Policlinico San Martino, Genoa, Italy

    Laura Emionite

  7. Department of Health Science, University of Genoa, Genoa, Italy

    Matteo Bauckneht & Silvia Morbelli

  8. Department of Integrated Surgical and Diagnostic Sciences (DISC), University of Genoa, Genoa, Italy

    Federica Grillo

  9. Department of Mathematics (DIMA), University of Genoa, Genoa, Italy

    Giacomo Caviglia

  10. Department of Pharmacy, Section of Biochemistry, University of Genoa, Genoa, Italy

    Isabella Panfoli

  11. Department of Experimental Medicine, Section of Physiology, University of Genoa, Genoa, Italy

    Fabio Benfenati

Authors
  1. Vanessa Cossu
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  2. Cecilia Marini
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  19. Gianmario Sambuceti
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Corresponding author

Correspondence to Gianmario Sambuceti.

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All procedures involving animals were performed in respect of the current National and International regulations and were reviewed and approved by the Licensing and Animal Welfare Body of the IRCCS Ospedale Policlinico San Martino, Genoa, Italy and by the Italian Ministry of Health.

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Cossu, V., Marini, C., Piccioli, P. et al. Obligatory role of endoplasmic reticulum in brain FDG uptake. Eur J Nucl Med Mol Imaging 46, 1184–1196 (2019). https://doi.org/10.1007/s00259-018-4254-2

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  • DOI: https://doi.org/10.1007/s00259-018-4254-2

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