Metabolic sensing and the brain: who, what, where, and how?

Abstract

Unique subpopulations of specialized metabolic sensing neurons reside in a distributed network throughout the brain and respond to alterations in ambient levels of various metabolic substrates by altering their activity. Variations in local brain substrate levels reflect their transport across the blood- and cerebrospinal-brain barriers as well as local production by astrocytes. There are a number of mechanisms by which such metabolic sensing neurons alter their activity in response to changes in substrate levels, but it is clear that these neurons cannot be considered in isolation. They are heavily dependent on astrocyte and probably tanycyte metabolism and function but also respond to hormones (e.g. leptin and insulin) and cytokines that cross the blood-brain barrier from the periphery as well as hard-wired neural inputs from metabolic sensors in peripheral sites such as the hepatic portal vein, gastrointestinal tract, and carotid body. Thus, these specialized neurons are capable of monitoring and integrating multiple signals from the periphery as a means of regulating peripheral energy homeostasis.

Fig. 1.

Model of the interrelationship among various types of glucosensing neurons, cerebral microvessels, astrocytes, and tanycytes within the ventromedial (VMH) and lateral hypothalamic area (LHA). GE neurons increase their activity in response to increasing glucose levels by the following: 1) glucose transport via Glut3 transporters, phosphorylation by GK, production of ATP by mitochondrial oxidation, and inactivation of the K_ATP channel leading to membrane depolarization; 2) interaction with the sodium glucose co-transporter (SGLT) and metabolism-independent generation of an electrogenic potential; and 3) use of astrocyte-derived lactate, which is transported into neurons by monocarboxylate transporter 2 (MCT2) with conversion to pyruvate for oxidative production of ATP and inactivation of the K_ATP channel. GI neurons are activated by the following: 1) low levels of glucose and GK-modulated phosphorylation leading to increased AMP levels, activation of AMPK, and closure of a chloride channel (possibly cystic fibrosis transmembrane receptor); and 2) activation of a K⁺ leak channel generating a metabolism-independent electrogenic potential. Tanycytes contain GK and Glut2 and may provide trophic support for glucosensing neurons. 3v, Third ventricle.

Fig. 2.

Vimentin-expressing tanycytes line the lower third of the third ventricle and send processes into the ARC and VMN. Presumptive GK-expressing glucosensing neurons lie in close approximation to these processes, suggesting a supportive role in neuronal glucosensing. DAPI, 4′,6′-Diamidino-2-phenylindole.