Orexin neurons as conditional glucosensors: paradoxical regulation of sugar sensing by intracellular fuels

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Non-technical summary

Brain orexin/hypocretin neurons stimulate wakefulness, feeding, reward-seeking and healthy glucose balance. The activity of orexin neurons is tightly regulated by several hormones, neurotransmitters and nutrients. Intriguingly, elevated glucose concentration can block or silence the activity of orexin neurons. We identified an unexpected way to control these effects of glucose on orexin neurons. We found that supplying orexin neurons with other energy-related molecules, such as pyruvate and lactate, can stop glucose from blocking orexin neurons. We hypothesize that orexin neurons only ‘see’ glucose changes when the levels of other energy molecules are low, whereas high energy levels can stop glucose from regulating orexin cells. This may shed new light on understanding how the brain is influenced by changes in glucose levels during different metabolic situations, such as fasting, eating different diets, or in disease states such as diabetes and obesity.

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.

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