ATP-mediated glucosensing by hypothalamic tanycytes

Non-technical summary The hypothalamus contains key neural circuits involved in the control of feeding and energy balance. Stimulated by the inexorable rise of obesity, there has been intense study of these neural circuits. However, the possible role of non-neuronal cells in the brain has not been extensively considered. We now demonstrate that hypothalamic tanycytes, cells that lie at the interface between the ventricular cerebrospinal fluid and the brain parenchyma, respond to both neuron-derived and circulating agents that signal energy status and arousal. Our study therefore suggests that tanycytes should now be considered as active signalling cells in the brain capable of responding to several types of input and having the potential to participate in the control of energy balance and feeding.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 Ca2+; 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 Ca2+ 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.