Vanessa Cossu1, Cecilia Marini1,2, Patrizia Piccioli3, Anna Rocchi4, Silvia Bruno5, Anna Maria Orengo1, Laura Emionite6, Matteo Bauckneht1,7, Federica Grillo8, Selene Capitanio1, Enrica Balza3, Nikola Yosifov1, Patrizia Castellani3, Giacomo Caviglia9, Isabella Panfoli10, Silvia Morbelli1,7, Silvia Ravera5, Fabio Benfenati4,11, Gianmario Sambuceti12,13. 1. Nuclear Medicine, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, Italy. 2. CNR Institute of Molecular Bioimaging and Physiology (IBFM), Milan, Italy. 3. Cell Biology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy. 4. Center for Synaptic Neuroscience and Technology, Italian Institute of Technology (IIT), Genoa, Italy. 5. Department of Experimental Medicine, University of Genoa, Genoa, Italy. 6. Animal Facility, IRCCS Ospedale Policlinico San Martino, Genoa, Italy. 7. Department of Health Science, University of Genoa, Genoa, Italy. 8. Department of Integrated Surgical and Diagnostic Sciences (DISC), University of Genoa, Genoa, Italy. 9. Department of Mathematics (DIMA), University of Genoa, Genoa, Italy. 10. Department of Pharmacy, Section of Biochemistry, University of Genoa, Genoa, Italy. 11. Department of Experimental Medicine, Section of Physiology, University of Genoa, Genoa, Italy. 12. Nuclear Medicine, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, Italy. Sambuceti@unige.it. 13. CNR Institute of Molecular Bioimaging and Physiology (IBFM), Milan, Italy. Sambuceti@unige.it.
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.
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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