Neuronal Glucosensing
What Do We Know After 50 Years?
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- FIG. 1.
Location of ARC and VMN neurons relative to blood, CSF, and brain glucose levels. ARC neurons are potentially exposed to glucose from the CSF, which diffuses across the β1-tanycytes lining the IIIrd cerebral ventricle; blood glucose, which diffuses across the fenestrated capillaries in the median eminence; and glucose, which is transported across the blood-brain barrier. Some of these neurons synapse with VMN neurons, which are exposed primarily to glucose transported from blood and diffusing from CSF.
- FIG. 2.
Hypothetical model of a GE neuron and its relationship to adjacent astrocytes. Glucose is transported across the microvessel by GLUT1 and enters either the astrocyte by GLUT1 transport or the extracellular space, where it is transported into a GE neuron by GLUT3. GK is localized together with adjacent mitochondria beneath the plasma membrane containing a KATP channel. ATP formed in this microenvironment binds to the KATP channel, which inactivates (closes) the channel leading to membrane depolarization, entry of calcium through a voltage-dependent calcium channel (VDCC), and, in many cases, increased neuronal activity. Local changes in ambient glucose concentrations at the axon terminal can also inactivate KATP channels with release of neurotransmitters such as glutamate. Hexokinase I (HKI) regulates the formation of ATP for general metabolic functions of the neurons. Glucose transported into astrocytes is stored as glycogen. Glycogenolysis produces lactate that is transported by an MCT1 transporter into the extracellular space and then into the neuron through MCT1. This lactate is converted to pyruvate by LDH and oxidized in the mitochondria with resultant ATP production. Under low ambient glucose conditions, this astrocyte-derived lactate can raise neuronal ATP levels sufficiently to close the KATP channel, leading to neuronal activation.
- FIG. 3.
Leptin (Lep) increases intracellular calcium oscillations in a dissociated VMN GE neuron that expresses the OB-Rb receptor. Addition of 10 nmol/l leptin to a GE neuron that was inactive at 0.5 mmol/l glucose (G) leads to activation (increased intracellular Ca+2 oscillations). Single-cell RT-PCR of the cytoplasmic contents of this neuron demonstrated that it expressed mRNA for GK, the signaling form of the leptin receptor (OB-Rb), the insulin receptor (INS-R), GLUT3, and GAD (which defines it as GABAergic) (23,96).
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- Article
- Abstract
- GLUCOSENSING NEURONS INTEGRATE A VARIETY OF TIME- AND CONCENTRATION-DEPENDENT PATTERNS OF GLUCOSE CHANGE
- HOW IS GLUCOSE SENSED?
- GLUCOSENSING NEURONS AS METABOLIC SENSORS
- WHAT PHYSIOLOGICAL FUNCTIONS ARE REGULATED BY GLUCOSENSING NEURONS?
- HOW IS GLUCOSENSING ALTERED BY DISEASE?
- SUMMARY AND CONCLUSIONS: WHAT HAVE WE LEARNED AND WHAT REMAINS TO BE LEARNED?
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