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Metabolism-Independent Sugar Sensing in Central Orexin Neurons

¹ Department of Pharmacology, University of Cambridge, Cambridge, U.K
² Clinical Institute, Aarhus University Hospital, Skejby Sygehus, Denmark
³ Department of Clinical Neurology, University of Oxford, Oxford, U.K

Corresponding author: Dr. Denis Burdakov, dib22{at}cam.ac.uk

OBJECTIVE— Glucose sensing by specialized neurons of the hypothalamus is vital for normal energy balance. In many glucose-activated neurons, glucose metabolism is considered a critical step in glucose sensing, but whether glucose-inhibited neurons follow the same strategy is unclear. Orexin/hypocretin neurons of the lateral hypothalamus are widely projecting glucose-inhibited cells essential for normal cognitive arousal and feeding behavior. Here, we used different sugars, energy metabolites, and pharmacological tools to explore the glucose-sensing strategy of orexin cells.

RESEARCH DESIGN AND METHODS— We carried out patch-clamp recordings of the electrical activity of individual orexin neurons unambiguously identified by transgenic expression of green fluorescent protein in mouse brain slices.

RESULTS— We show that 1) 2-deoxyglucose, a nonmetabolizable glucose analog, mimics the effects of glucose; 2) increasing intracellular energy fuel production with lactate does not reproduce glucose responses; 3) orexin cell glucose sensing is unaffected by glucokinase inhibitors alloxan, D-glucosamine, and N-acetyl-D-glucosamine; and 4) orexin glucosensors detect mannose, D-glucose, and 2-deoxyglucose but not galactose, L-glucose, -methyl-D-glucoside, or fructose.

CONCLUSIONS— Our new data suggest that behaviorally critical neurocircuits of the lateral hypothalamus contain glucose detectors that exhibit novel sugar selectivity and can operate independently of glucose metabolism.

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