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      Amino acid sensing in hypothalamic tanycytes via umami taste receptors

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          Abstract

          Objective

          Hypothalamic 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.

          Methods

          Ca 2+ 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.

          Results

          Amino acids such as Arg, Lys, and Ala evoke Ca 2+ 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.

          Conclusion

          Two 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.

          Graphical abstract

          Highlights

          • Hypothalamic tanycytes can detect amino acids in cerebrospinal fluid.

          • The mechanism is taste receptor-dependent.

          • Tas1r1/Tas1r3 mediates responses to l-arginine and l-lysine.

          • mGluR4 mediates responses to l-alanine and partially those of l-lysine.

          • ATP release from tanycytes evoked by amino acids reaches into the arcuate nucleus.

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          Most cited references53

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          An amino-acid taste receptor.

          The sense of taste provides animals with valuable information about the nature and quality of food. Mammals can recognize and respond to a diverse repertoire of chemical entities, including sugars, salts, acids and a wide range of toxic substances. Several amino acids taste sweet or delicious (umami) to humans, and are attractive to rodents and other animals. This is noteworthy because L-amino acids function as the building blocks of proteins, as biosynthetic precursors of many biologically relevant small molecules, and as metabolic fuel. Thus, having a taste pathway dedicated to their detection probably had significant evolutionary implications. Here we identify and characterize a mammalian amino-acid taste receptor. This receptor, T1R1+3, is a heteromer of the taste-specific T1R1 and T1R3 G-protein-coupled receptors. We demonstrate that T1R1 and T1R3 combine to function as a broadly tuned L-amino-acid sensor responding to most of the 20 standard amino acids, but not to their D-enantiomers or other compounds. We also show that sequence differences in T1R receptors within and between species (human and mouse) can significantly influence the selectivity and specificity of taste responses.
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            Neurogenesis in the hypothalamus of adult mice: potential role in energy balance.

            Ciliary neurotrophic factor (CNTF) induces weight loss in obese rodents and humans, and for reasons that are not understood, its effects persist after the cessation of treatment. Here we demonstrate that centrally administered CNTF induces cell proliferation in feeding centers of the murine hypothalamus. Many of the newborn cells express neuronal markers and show functional phenotypes relevant for energy-balance control, including a capacity for leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3). Coadministration of the mitotic blocker cytosine-beta-d-arabinofuranoside (Ara-C) eliminates the proliferation of neural cells and abrogates the long-term, but not the short-term, effect of CNTF on body weight. These findings link the sustained effect of CNTF on energy balance to hypothalamic neurogenesis and suggest that regulated hypothalamic neurogenesis in adult mice may play a previously unappreciated role in physiology and disease.
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              Tanycytes of the Hypothalamic Median Eminence Form a Diet-Responsive Neurogenic Niche

              Adult hypothalamic neurogenesis has been recently reported, but the cell of origin and function of these newborn neurons are unknown. We utilize genetic fate mapping to show that median eminence tanycytes generate newborn neurons; blocking this neurogenesis alters weight and metabolic activity in adult mice. These findings describe a previously unreported neurogenic niche within the mammalian hypothalamus with important implications for metabolism.
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                Author and article information

                Contributors
                Journal
                Mol Metab
                Mol Metab
                Molecular Metabolism
                Elsevier
                2212-8778
                14 September 2017
                November 2017
                14 September 2017
                : 6
                : 11
                : 1480-1492
                Affiliations
                [1 ]School of Life Sciences, University of Warwick, Coventry, CV4 7AL, UK
                [2 ]Department of Molecular Genetics, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany
                Author notes
                []Corresponding author. School of Life Sciences, Gibbet Hill Rd, Coventry, CV4 7AL, UK.School of Life SciencesGibbet Hill RdCoventryCV4 7ALUK n.e.dale@ 123456warwick.ac.uk
                [3]

                Present address: Dept. of Chemistry “G. Ciamician”, University of Bologna, Via Selmi 2, 40126, Bologna, Italy.

                Article
                S2212-8778(17)30537-9
                10.1016/j.molmet.2017.08.015
                5681271
                29107294
                b7aea37c-1d05-43b9-ac00-0d560ac17028
                © 2017 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 25 July 2017
                : 25 August 2017
                : 30 August 2017
                Categories
                Original Article

                hypothalamic tanycytes,taste receptors,tas1r1/tas1r3,mglur4,amino acids,appetite

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