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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, 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.

Original publication




Journal article



Publication Date





2569 - 2576


Acetylglucosamine, Alloxan, Animals, Carbohydrates, Deoxyglucose, Energy Metabolism, Fructose, Galactose, Glucosamine, Green Fluorescent Proteins, Hypothalamic Area, Lateral, Intracellular Signaling Peptides and Proteins, Lactic Acid, Mannose, Membrane Potentials, Methylglucosides, Mice, Mice, Transgenic, Neurons, Neuropeptides, Orexins, Patch-Clamp Techniques, Tolbutamide