Wired on sugar: the role of the CNS in the regulation of glucose homeostasis

Recent findings indicate that neuronal populations in the hypothalamus that had already been identified as being crucial to the regulation of energy balance are also essential for the regulation of glucose homeostasis.The melanocortin system within the arcuate nucleus (ARC) of the hypothalamus has an important role in the integration of signals from circulating hormones to maintain both energy and glucose homeostasis.ATP-sensitive potassium channels, ATP-activated protein kinase and mammalian target of rapamycin act as 'general' fuel sensors — they sense changes in overall energy status through changes in ATP. The sensing of fuel and ATP specifically within the hypothalamus has the capacity to modulate both glucose and energy homeostasis.Neuronal populations outside the ARC (including steroidogenic factor 1 neurons within the ventromedial hypothalamus) and multiple populations of neurons within the hindbrain (melanocortin receptor 4-expressing neurons in the sympathetic nervous system and NMDA receptor-expressing neurons) contribute to the regulation of glucose and energy homeostasis.Within the gut, cholecystokinin and glucagon-like peptide 1 provide a conduit for CNS-induced regulation of energy and glucose homeostasis.A key outstanding question in the field is whether the neuronal circuits that are crucial for body weight regulation and that may be dysregulated in obesity also contribute to the poor glucose homeostasis that eventually results in type 2 diabetes mellitus.New strategies such as optogenetics and DREADD (designer receptors exclusively activated by designer drugs) provide an avenue for further understanding the crossroads of glucose and energy homeostasis.