All dressed up and nowhere to go - finding the glucosensing party for hypothalamic tancytes
Lead Research Organisation:
University of Warwick
Department Name: Biological Sciences
Abstract
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Technical Summary
The brain senses the levels of glucose in blood and cerebrospinal fluid (CSF). This important component of autonomic function is partly mediated by neurons in the hypothalamus that respond to changes in the physiological levels of glucose. The responsiveness of ‘glucosensitive‘ neurons is modified in models of obesity. These neurons project to effector areas that control neuroendocrine, metabolic and autonomic functions, and ultimately energy homoeostasis. Altered glucosensing in the brain may thus contribute to obesity - a major and growing problem in the health of developed nations. However another major potential but neglected component of glucosensing exists in the hypothalamus.
Strange cells, called tanycytes, contact the CSF of the 3rd ventricle and send a process into the hypothalamus. Although they contain all of the molecular components required for glucosensing and are highly likely to be an active player in brain glucosensing, the putative output signal from tanycytes to neurons is completely unknown. The tanycytes are thus apparently unconnected to the brain networks involved in glucosensing and energy homoeostasis. Current thinking on glucosensing in the brain is likely to be fundamentally incomplete.
My aim is to investigate the output signals from tanycytes, their communication with neurons, the integration of tanycytic and neuronal glucosensing signals and ultimately their contribution to physiological energy homoeostasis. This work will revolutionize thinking about glucosensing in the brain by integrating a major new non-neuronal class of cell into the detection of blood/CSF glucose and the downstream adaptive responses.
Selective manipulation of tanycyte signalling based on my findings could inform new strategies for the treatment of obesity and diabetes. I propose both a radical new hypothesis and an innovative approach to testing it. I suggest that glucosensing lies within a general paradigm of brain chemosensing exemplified by my recent work on CO2 chemosensing - whereby CO2 sensory cells release ATP to excite neurons and evoke adaptive changes in breathing.
I propose that tanycytes release ATP to signal changes in glucose levels to neurons in the hypothalamus. I will test this hypothesis by using novel microelectrode biosensors to measure ATP release in response to alterations of glucose in likely areas of the hypothalamus - thus providing information about the locus, dynamics and mechanisms of tanycyte signalling.
This hypothesis is too speculative to be funded by conventional streams; furthermore I am proposing to enter a new area of investigation in which I have no prior experience. Nevertheless I believe fresh ideas and technology from outside the glucosensing field will yield great benefits and advance knowledge rapidly.
Strange cells, called tanycytes, contact the CSF of the 3rd ventricle and send a process into the hypothalamus. Although they contain all of the molecular components required for glucosensing and are highly likely to be an active player in brain glucosensing, the putative output signal from tanycytes to neurons is completely unknown. The tanycytes are thus apparently unconnected to the brain networks involved in glucosensing and energy homoeostasis. Current thinking on glucosensing in the brain is likely to be fundamentally incomplete.
My aim is to investigate the output signals from tanycytes, their communication with neurons, the integration of tanycytic and neuronal glucosensing signals and ultimately their contribution to physiological energy homoeostasis. This work will revolutionize thinking about glucosensing in the brain by integrating a major new non-neuronal class of cell into the detection of blood/CSF glucose and the downstream adaptive responses.
Selective manipulation of tanycyte signalling based on my findings could inform new strategies for the treatment of obesity and diabetes. I propose both a radical new hypothesis and an innovative approach to testing it. I suggest that glucosensing lies within a general paradigm of brain chemosensing exemplified by my recent work on CO2 chemosensing - whereby CO2 sensory cells release ATP to excite neurons and evoke adaptive changes in breathing.
I propose that tanycytes release ATP to signal changes in glucose levels to neurons in the hypothalamus. I will test this hypothesis by using novel microelectrode biosensors to measure ATP release in response to alterations of glucose in likely areas of the hypothalamus - thus providing information about the locus, dynamics and mechanisms of tanycyte signalling.
This hypothesis is too speculative to be funded by conventional streams; furthermore I am proposing to enter a new area of investigation in which I have no prior experience. Nevertheless I believe fresh ideas and technology from outside the glucosensing field will yield great benefits and advance knowledge rapidly.
