title: Orexin neurons as conditional glucosensors: paradoxical regulation of sugar sensing by intracellular fuels.
abstract: Central orexin/hypocretin neurons promote wakefulness, feeding and reward-seeking, and control blood glucose levels by regulating sympathetic outflow to the periphery. Glucose itself directly suppresses the electrical activity and cytosolic calcium levels of orexin cells. Recent in vitro studies suggested that glucose inhibition of orexin cells may be mechanistically unusual, because it persists under conditions where glucose metabolism is unlikely. To investigate this further, and to clarify whether background metabolic state regulates orexin cell glucosensing, here we analysed glucose responses of orexin cells in mouse brain slices, in the presence and absence of metabolic inhibitors and physiological energy substrates. Consistent with their documented insensitivity to glucokinase inhibitors, the glucose responses of orexin cells persisted in the presence of the mitochondrial poison oligomycin or the glial toxin fluoroacetate. Unexpectedly, in the presence of oligomycin, the magnitude of the glucose response was significantly enhanced. In turn, 2-deoxyglucose, a non-metabolizable glucose analogue, elicited larger responses than glucose. Conversely, intracellular pyruvate dose-dependently suppressed the glucose responses, an effect that was blocked by oligomycin. The glucose responses were also suppressed by intracellular lactate and ATP. Our new data suggest that other energy substrates not only fail to mimic the orexin glucose response, but paradoxically suppress it in a metabolism-dependent manner. We propose that this unexpected intrinsic property of orexin cells allows them to act as 'conditional glucosensors' that preferentially respond to glucose during reduced background energy levels.
authors: Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
authors: Anne
authors: A
authors: Venner
authors: Mahesh M
authors: MM
authors: Karnani
authors: J Antonio
authors: JA
authors: Gonzalez
authors: Lise T
authors: LT
authors: Jensen
authors: Lars
authors: L
authors: Fugger
authors: Denis
authors: D
authors: Burdakov
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology*; D005463:Fluoroacetates / Q000494:pharmacology; D005947:Glucose / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors; D009474:Neurons / Q000502:physiology*; D009479:Neuropeptides / Q000502:physiology*; D009840:Oligomycins / Q000494:pharmacology; D000068797:Orexins; D018408:Patch-Clamp Techniques; D019289:Pyruvic Acid / Q000378:metabolism
chemical_list: D005463:Fluoroacetates; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D009840:Oligomycins; D000068797:Orexins; D019344:Lactic Acid; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D025261:Mitochondrial Proton-Translocating ATPases; D005947:Glucose