Glucose-sensing neurons of the hypothalamus

Abstract

Specialized subgroups of hypothalamic neurons exhibit specific excitatory or inhibitory electrical responses to changes in extracellular levels of glucose. Glucose-excited neurons were traditionally assumed to employ a 'beta-cell' glucose-sensing strategy, where glucose elevates cytosolic ATP, which closes KATP channels containing Kir6.2 subunits, causing depolarization and increased excitability. Recent findings indicate that although elements of this canonical model are functional in some hypothalamic cells, this pathway is not universally essential for excitation of glucose-sensing neurons by glucose. Thus glucose-induced excitation of arcuate nucleus neurons was recently reported in mice lacking Kir6.2, and no significant increases in cytosolic ATP levels could be detected in hypothalamic neurons after changes in extracellular glucose. Possible alternative glucose-sensing strategies include electrogenic glucose entry, glucose-induced release of glial lactate, and extracellular glucose receptors. Glucose-induced electrical inhibition is much less understood than excitation, and has been proposed to involve reduction in the depolarizing activity of the Na+/K+ pump, or activation of a hyperpolarizing Cl- current. Investigations of neurotransmitter identities of glucose-sensing neurons are beginning to provide detailed information about their physiological roles. In the mouse lateral hypothalamus, orexin/hypocretin neurons (which promote wakefulness, locomotor activity and foraging) are glucose-inhibited, whereas melanin-concentrating hormone neurons (which promote sleep and energy conservation) are glucose-excited. In the hypothalamic arcuate nucleus, excitatory actions of glucose on anorexigenic POMC neurons in mice have been reported, while the appetite-promoting NPY neurons may be directly inhibited by glucose. These results stress the fundamental importance of hypothalamic glucose-sensing neurons in orchestrating sleep-wake cycles, energy expenditure and feeding behaviour.

Figure 1

Model for how actions of glucose on neurons of the lateral hypothalamus may regulate sleep and feeding behaviour. (a) When body energy resources are low, extracellular glucose concentration falls. This increases the electrical activity of orexin neurons (which are inhibited by glucose), but suppresses the excitability of MCH neurons. Consequent increased release of orexin and decreased release of MCH stimulates wakefulness, appetite and activity, leading to foraging and feeding. (b) When body energy supplies are high, elevated extracellular glucose inhibits orexin neurons and activates MCH neurons, leading to increased sleepiness, and decreased metabolism and activity. See test for details.

Figure 2

Multiple pathways are likely to be involved in the modulation of the electrical activity of hypothalamic neurons by glucose. (a) Glucose, acting as an energy substrate, can alter neuronal electrical activity by influencing energy metabolism inside neurons and glia. (b) Glucose, acting as an extracellular signalling messenger, can also activate specific glucose receptors that control membrane ion fluxes, or can itself be transported by electrogenic transporters. Which of these general mechanisms is dominant in different glucose-sensing neurons remains to be determined. See text for details.