Hypothalamic glucosensing and its inhibition by GK knockdown in tanycytes. Model of glucosensing based on the metabolic interaction between tanycytes and AN neurons. Tanycytes are a specialized ependymal cell, localized in the lower parts of the ventricular walls and the floor of the 3V. α and β1-tanycytes line the infundibular recess, and their basal projections reach orexigenic and anorexigenic AN neurons. β2-tanycytes cover the floor of the 3V and extend their projections inside the ME and regulate the permeability properties of the fenestrated capillaries of the ME. Hyperglycemia results in increased glucose concentrations in the 3V, which affects GK-positive β1-tanycytes. These glial cells sense the increased glucose by the presence of GLUT2 and GK. The GK activity could be regulated by GKRP and its nuclear compartmentalization. Lactate released by tanycytes could activate neurons of AN, generating a satiety response. GK inhibition represses the glucosensing circuit, causing an altered feeding behavior. 3V, third ventricle; ME, median eminence; CSF, cerebrospinal fluid; GK, glucokinase; AN, arcuate nucleus; MCT, monocarboxylate transporter.