Metabolism-independent sugar sensing in central orexin neurons

Abstract

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 behaviour. 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 GFP in mouse brain slices.

RESULTS: We show that 1) 2-deoxyglucose, a non-metabolizable glucose analogue, 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, [scap]d[r]-glucosamine, and N-acetyl-[scap]d[r]-glucosamine; 4) Orexin glucosensors detect mannose, [scap]d[r]-glucose, and 2-deoxyglucose, but not by galactose, [scap]l[r]-glucose, α-methyl-[scap]d[r]-glucoside, or fructose.

CONCLUSION: 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.