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

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.