Metabolism-independent sugar sensing in central orexin neurons.
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.


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, alpha-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.
González
J Antonio
JA
Department of Pharmacology, University of Cambridge, Cambridge, UK.
Jensen
Lise T
LT
Fugger
Lars
L
Burdakov
Denis
D
D000117:Acetylglucosamine / Q000494:pharmacology; D000496:Alloxan / Q000494:pharmacology; D000818:Animals; D002241:Carbohydrates / Q000494:pharmacology*; D003847:Deoxyglucose / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D005632:Fructose / Q000494:pharmacology; D005690:Galactose / Q000494:pharmacology; D005944:Glucosamine / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007026:Hypothalamic Area, Lateral / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D019344:Lactic Acid / Q000494:pharmacology; D008358:Mannose / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008757:Methylglucosides / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D000068797:Orexins; D018408:Patch-Clamp Techniques; D014044:Tolbutamide / Q000494:pharmacology
D002241:Carbohydrates; D047908:Intracellular Signaling Peptides and Proteins; D008757:Methylglucosides; D009479:Neuropeptides; D000068797:Orexins; D049452:Green Fluorescent Proteins; D005632:Fructose; D019344:Lactic Acid; C027020:methylglucoside; D000496:Alloxan; D014044:Tolbutamide; D003847:Deoxyglucose; D005944:Glucosamine; D008358:Mannose; D000117:Acetylglucosamine; D005690:Galactose