ATP-mediated glucosensing by hypothalamic tanycytes

ABSTRACT: The brain plays a vital role in the regulation of food intake, appetite and ultimately bodyweight. Neurons in the hypothalamic arcuate nucleus, the ventromedial hypothalamic nuclei (VMH) and the lateral hypothalamus are sensitive to a number of circulating signals such as leptin, grehlin, insulin and glucose. These neurons are part of a network that integrates this information to regulate feeding and appetite. Hypothalamic tanycytes contact the cerebral spinal fluid of the third ventricle and send processes into the parenchyma. A subset of tanycytes are located close to, and send processes towards, the hypothalamic nuclei that contain neurons that are glucosensitive and are involved in the regulation of feeding. Nevertheless the signalling properties of tanycytes remain largely unstudied. We now demonstrate that tanycytes signal via waves of intracellular Ca(2+); they respond strongly to ATP, histamine and acetylcholine – transmitters associated with the drive to feed. Selective stimulation by glucose of tanycyte cell bodies evokes robust ATP-mediated Ca(2+) responses. Tanycytes release ATP in response to glucose. Furthermore tanycytes also respond to non-metabolisable analogues of glucose. Although tanycytes have been proposed as glucosensors, our study provides the first direct demonstration of this hypothesis. Tanycytes must therefore now be considered as active signalling cells within the brain that can respond to a number of neuronally derived and circulating transmitters and metabolites.