title: Hypothalamic UDP Increases in Obesity and Promotes Feeding via P2Y6-Dependent Activation of AgRP Neurons.
abstract: Activation of orexigenic AgRP-expressing neurons in the arcuate nucleus of the hypothalamus potently promotes feeding, thus defining new regulators of AgRP neuron activity could uncover potential novel targets for obesity treatment. Here, we demonstrate that AgRP neurons express the purinergic receptor 6 (P2Y6), which is activated by uridine-diphosphate (UDP). In vivo, UDP induces ERK phosphorylation and cFos expression in AgRP neurons and promotes action potential firing of these neurons in brain slice recordings. Consequently, central application of UDP promotes feeding, and this response is abrogated upon pharmacologic or genetic inhibition of P2Y6 as well as upon pharmacogenetic inhibition of AgRP neuron activity. In obese animals, hypothalamic UDP content is elevated as a consequence of increased circulating uridine concentrations. Collectively, these experiments reveal a potential regulatory pathway in obesity, where peripheral uridine increases hypothalamic UDP concentrations, which in turn can promote feeding via PY6-dependent activation of AgRP neurons.
authors.affiliation: Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism, Gleueler Str. 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany.
authors.forename: Sophie M
authors.initials: SM
authors.lastname: Steculorum
authors.affiliation: Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany; Biocenter, Institute for Zoology, University of Cologne, Zülpicher Str. 47a, 50674 Cologne, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Paeger
authors.affiliation: Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany; Biocenter, Institute for Zoology, University of Cologne, Zülpicher Str. 47a, 50674 Cologne, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Bremser
authors.affiliation: Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism, Gleueler Str. 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Evers
authors.affiliation: Max Planck Institute for Biology of Ageing, Cologne, Joseph-Stelzmann-Str. 9B 50931 Cologne, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Hinze
authors.affiliation: Department of Pneumology, Freiburg University Medical Center, Albert-Ludwigs-University, Hugstetter Str. 49, 79106 Freiburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Idzko
authors.affiliation: Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany; Biocenter, Institute for Zoology, University of Cologne, Zülpicher Str. 47a, 50674 Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kloppenburg
authors.affiliation: Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism, Gleueler Str. 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany; National Center for Diabetes Research (DZD), Ingolstädter Land Str. 1, 85764 Neuherberg, Germany. Electronic address: bruening@sf.mpg.de.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
mesh_terms: D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D001069:Appetite Regulation; D004195:Disease Models, Animal; D007031:Hypothalamus / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D014530:Uridine Diphosphate / Q000378:metabolism*
chemical_list: D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D018048:Receptors, Purinergic P2; C099845:purinoceptor P2Y6; D014530:Uridine Diphosphate