GK, which catalyzes the high-Km phosphorylation of glucose, is a crucial enzyme in glucose homeostasis in different tissues involved in glucosensing. It is important to highlight that hexokinase I is also expressed in glucose-sensing cells from the VMH. However, its higher affinity for glucose (Km of 1 mM) and kinetic properties prevent hexokinase I from modulating its activity according to changes in glucose levels. Therefore, hexokinase I from the VMH seems to be involved in the continuous generation of ATP regardless of changes in extracellular glucose concentrations whereas GK acts as a glucose sensor32, 33. Studies in GK heterozygous knockout mice have attributed a major role for GK in food intake as well as in reproductive functions34. In a manner similar to that reported for pancreatic β-cells, GK is required for active glycolysis in β1-tanycytes. An increase in glucose concentration generates an enhanced glycolytic flux, which leads to ATP release in cultured tanycytes3. ATP activates P2Y receptors, which provokes an increase in cytosolic calcium levels at the expense of intracellular calcium sources3. Interestingly, ATP release and intracellular calcium increase were inhibited in experiments carried out with alloxan, a GK pharmacological inhibitor, demonstrating the importance of GK in this glucose-driven signaling mechanism3.