Glucosensing neurons do more than just sense glucose

Abstract

The brain regulates energy homeostasis by balancing energy intake, expenditure and storage. To accomplish this, it has evolved specialized neurons that receive and integrate afferent neural and metabolic signals conveying information about the energy status of the body. These sensor–integrator–effector neurons are located in brain areas involved in homeostatic functions such as the hypothalamus, locus coeruleus, basal ganglia, limbic system and nucleus tractus solitarius. The ability to sense and regulate glucose metabolism is critical because of glucose's primacy as a metabolic substrate for neural function. Most neurons use glucose as an energy substrate, but glucosensing neurons also use glucose as a signaling molecule to regulate neuronal firing and transmitter release. There are two types of glucosensing neurons that either increase (glucose responsive, GR) or decrease (glucose sensitive, GS) their firing rate as brain glucose levels rise. Little is known about the mechanism by which GS neurons sense glucose. However, GR neurons appear to function much like the pancreatic β-cell where glycolysis regulates the activity of an ATP-sensitive K⁺ (K_ATP) channel. The K_ATP channel is composed of four pore-forming units (Kir6.2) and four sulfonylurea binding sites (SUR). Glucokinase (GK) appears to modulate K_ATP channel activity via its gatekeeper role in the glycolytic production of ATP. Thus, GK may serve as a marker for GR neurons. Neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus are critical components of the energy homeostasis pathways in the brain. Both express Kir6.2 and GK, as well as leptin receptors. They also receive visceral neural and intrinsic neuropeptide and transmitter inputs. Such metabolism-related signals can summate upon K_ATP channel activity which then alters membrane potential, neuronal firing rate and peptide/transmitter release. The outputs of these neurons are integral components of effector systems which regulate energy homeostasis. Thus, arcuate NPY and POMC neurons are probably prototypes of this important class of sensor–integrator–effector neurons.