title: Inhibition of P2Y6 Signaling in AgRP Neurons Reduces Food Intake and Improves Systemic Insulin Sensitivity in Obesity.
abstract: Uridine-diphosphate (UDP) and its receptor P2Y6 have recently been identified as regulators of AgRP neurons. UDP promotes feeding via activation of P2Y6 receptors on AgRP neurons, and hypothalamic UDP concentrations are increased in obesity. However, it remained unresolved whether inhibition of P2Y6 signaling pharmacologically, globally, or restricted to AgRP neurons can improve obesity-associated metabolic dysfunctions. Here, we demonstrate that central injection of UDP acutely promotes feeding in diet-induced obese mice and that acute pharmacological blocking of CNS P2Y6 receptors reduces food intake. Importantly, mice with AgRP-neuron-restricted inactivation of P2Y6 exhibit reduced food intake and fat mass as well as improved systemic insulin sensitivity with improved insulin action in liver. Our results reveal that P2Y6 signaling in AgRP neurons is involved in the onset of obesity-associated hyperphagia and systemic insulin resistance. Collectively, these experiments define P2Y6 as a potential target to pharmacologically restrict both feeding and systemic insulin resistance in obesity.
authors.affiliation: Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 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-Strasse 26, 50931 Cologne, Germany.
authors.forename: Sophie Marie
authors.initials: SM
authors.lastname: Steculorum
authors.affiliation: Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 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-Strasse 26, 50931 Cologne, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Timper
authors.affiliation: Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 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-Strasse 26, 50931 Cologne, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Engström Ruud
authors.affiliation: Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 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-Strasse 26, 50931 Cologne, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Evers
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-Strasse 26, 50931 Cologne, Germany; Institute for Zoology, University of Cologne, Zülpicher Strasse 47b, 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-Strasse 26, 50931 Cologne, Germany; Institute for Zoology, University of Cologne, Zülpicher Strasse 47b, 50674 Cologne, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Bremser
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-Strasse 26, 50931 Cologne, Germany; Institute for Zoology, University of Cologne, Zülpicher Strasse 47b, 50674 Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kloppenburg
authors.affiliation: Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 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-Strasse 26, 50931 Cologne, Germany; National Center for Diabetes Research (DZD), Ingolstädter Land Strasse 1, 85764 Neuherberg, Germany. Electronic address: bruening@sf.mpg.de.
authors.forename: Jens Claus
authors.initials: JC
authors.lastname: Brüning
mesh_terms: D054369:Agouti-Related Protein / Q000378:metabolism*; D000818:Animals; D004032:Diet / Q000379:methods; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects*; D005247:Feeding Behavior / Q000187:drug effects; D006963:Hyperphagia / Q000188:drug therapy / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014530:Uridine Diphosphate / Q000494:pharmacology
chemical_list: D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D007328:Insulin; D018048:Receptors, Purinergic P2; C099845:purinoceptor P2Y6; D014530:Uridine Diphosphate
keywords: AgRP neurons; P2Y6; arcuate nucleus; diabetes; food intake; hypothalamus; insulin resistance; insulin sensitivity; obesity