Abstract
ObjectiveHypothalamic tanycytes are glial cells that line the wall of the third ventricle and contact the cerebrospinal fluid (CSF). While they are known to detect glucose in the CSF we now show that tanycytes also detect amino acids, important nutrients that signal satiety. MethodsCa2+ imaging and ATP biosensing were used to detect tanycyte responses to l-amino acids. The downstream pathway of the responses was determined using ATP receptor antagonists and channel blockers. The receptors were characterized using mice lacking the Tas1r1 gene, as well as an mGluR4 receptor antagonist. ResultsAmino acids such as Arg, Lys, and Ala evoke Ca2+ signals in tanycytes and evoke the release of ATP via pannexin 1 and CalHM1, which amplifies the signal via a P2 receptor dependent mechanism. Tanycytes from mice lacking the Tas1r1 gene had diminished responses to lysine and arginine but not alanine. Antagonists of mGluR4 greatly reduced the responses to alanine and lysine. ConclusionTwo receptors previously implicated in taste cells, the Tas1r1/Tas1r3 heterodimer and mGluR4, contribute to the detection of a range of amino acids by tanycytes in CSF.
Highlights
Amino acids have been long known to be the most efficient type of nutrient at satisfying hunger and providing an extended period of satiety [1]
Tanycytes only responded to amino acids when they were directly applied to the apical surface of the cells: puffing Arg onto the hypothalamic parenchyma
The sensitivity of tanycytes to different amino acids is relatively consistent with involvement of the Tas1r1/Tas1r3 umami receptor originally described in the taste buds of the tongue [20,21]
Summary
Amino acids have been long known to be the most efficient type of nutrient at satisfying hunger and providing an extended period of satiety [1]. Some well understood reasons for this effect are slower digestion of protein-rich foods, as well as their ability to keep blood glucose levels relatively constant, reducing food cravings that can otherwise occur soon after a meal. It has become evident over the past few decades that the brain is a key player in energy homeostasis, and amino acids can have a satiating effect even when the digestive system is bypassed. Lineage tracing studies have demonstrated that tanycytes can generate new neurons and glia, meaning that the neuronal networks of the hypothalamus are highly plastic and can be remodeled by diet [15]
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