Obligatory role of endoplasmic reticulum in brain FDG uptake

Vanessa Cossu, Cecilia Marini, Patrizia Piccioli, Anna Rocchi, Silvia Bruno, Anna Maria Orengo, Laura Emionite, Matteo Bauckneht, Federica Grillo, Selene Capitanio, Enrica Balza, Nikola Yosifov, Patrizia Castellani, Giacomo Caviglia, Isabella Panfoli, Silvia Morbelli, Silvia Ravera, Fabio Benfenati, Gianmario Sambuceti

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1184-1196
Number of pages13
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Volume46
Issue number5
DOIs
Publication statusPublished - May 1 2019

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Hexoses
Endoplasmic Reticulum
Oxidoreductases
Metformin
Fluorodeoxyglucose F18
Brain
Glucose
Phosphoric Monoester Hydrolases
Astrocytes
Neurons
Hexokinase
Enzymes
Confocal Microscopy
Lactic Acid
Pharmaceutical Preparations

Keywords

  • Brain imaging
  • Endoplasmic reticulum
  • FDG
  • Glucose metabolism
  • H6PD
  • PET/CT

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this

Obligatory role of endoplasmic reticulum in brain FDG uptake. / Cossu, Vanessa; Marini, Cecilia; Piccioli, Patrizia; Rocchi, Anna; Bruno, Silvia; Orengo, Anna Maria; Emionite, Laura; Bauckneht, Matteo; Grillo, Federica; Capitanio, Selene; Balza, Enrica; Yosifov, Nikola; Castellani, Patrizia; Caviglia, Giacomo; Panfoli, Isabella; Morbelli, Silvia; Ravera, Silvia; Benfenati, Fabio; Sambuceti, Gianmario.

In: European Journal of Nuclear Medicine and Molecular Imaging, Vol. 46, No. 5, 01.05.2019, p. 1184-1196.

Research output: Contribution to journalArticle

Cossu, V, Marini, C, Piccioli, P, Rocchi, A, Bruno, S, Orengo, AM, Emionite, L, Bauckneht, M, Grillo, F, Capitanio, S, Balza, E, Yosifov, N, Castellani, P, Caviglia, G, Panfoli, I, Morbelli, S, Ravera, S, Benfenati, F & Sambuceti, G 2019, 'Obligatory role of endoplasmic reticulum in brain FDG uptake', European Journal of Nuclear Medicine and Molecular Imaging, vol. 46, no. 5, pp. 1184-1196. https://doi.org/10.1007/s00259-018-4254-2
Cossu, Vanessa ; Marini, Cecilia ; Piccioli, Patrizia ; Rocchi, Anna ; Bruno, Silvia ; Orengo, Anna Maria ; Emionite, Laura ; Bauckneht, Matteo ; Grillo, Federica ; Capitanio, Selene ; Balza, Enrica ; Yosifov, Nikola ; Castellani, Patrizia ; Caviglia, Giacomo ; Panfoli, Isabella ; Morbelli, Silvia ; Ravera, Silvia ; Benfenati, Fabio ; Sambuceti, Gianmario. / Obligatory role of endoplasmic reticulum in brain FDG uptake. In: European Journal of Nuclear Medicine and Molecular Imaging. 2019 ; Vol. 46, No. 5. pp. 1184-1196.
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AU - Marini, Cecilia

AU - Piccioli, Patrizia

AU - Rocchi, Anna

AU - Bruno, Silvia

AU - Orengo, Anna Maria

AU - Emionite, Laura

AU - Bauckneht, Matteo

AU - Grillo, Federica

AU - Capitanio, Selene

AU - Balza, Enrica

AU - Yosifov, Nikola

AU - Castellani, Patrizia

AU - Caviglia, Giacomo

AU - Panfoli, Isabella

AU - Morbelli, Silvia

AU - Ravera, Silvia

AU - Benfenati, Fabio

AU - Sambuceti, Gianmario

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N2 - 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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