Inhibition of P2Y6 Signaling in AgRP Neurons Reduces Food Intake and Improves Systemic Insulin Sensitivity in Obesity
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-02-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112471730102X |
| _version_ | 1819101138926960640 |
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| author | Sophie Marie Steculorum Katharina Timper Linda Engström Ruud Nadine Evers Lars Paeger Stephan Bremser Peter Kloppenburg Jens Claus Brüning |
| author_facet | Sophie Marie Steculorum Katharina Timper Linda Engström Ruud Nadine Evers Lars Paeger Stephan Bremser Peter Kloppenburg Jens Claus Brüning |
| author_sort | Sophie Marie Steculorum |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T01:13:55Z |
| format | Article |
| id | doaj.art-eb59b1abb5ef4d2382782dbf987e61af |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-22T01:13:55Z |
| publishDate | 2017-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-eb59b1abb5ef4d2382782dbf987e61af2022-12-21T18:43:54ZengElsevierCell Reports2211-12472017-02-011871587159710.1016/j.celrep.2017.01.047Inhibition of P2Y6 Signaling in AgRP Neurons Reduces Food Intake and Improves Systemic Insulin Sensitivity in ObesitySophie Marie Steculorum0Katharina Timper1Linda Engström Ruud2Nadine Evers3Lars Paeger4Stephan Bremser5Peter Kloppenburg6Jens Claus Brüning7Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, GermanyDepartment of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, GermanyDepartment of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, GermanyDepartment of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, GermanyExcellence 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, GermanyExcellence 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, GermanyExcellence 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, GermanyDepartment of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, GermanyUridine-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.http://www.sciencedirect.com/science/article/pii/S221112471730102Xobesityinsulin sensitivityAgRP neuronsP2Y6diabetesfood intakehypothalamusarcuate nucleusinsulin resistance |
| spellingShingle | Sophie Marie Steculorum Katharina Timper Linda Engström Ruud Nadine Evers Lars Paeger Stephan Bremser Peter Kloppenburg Jens Claus Brüning Inhibition of P2Y6 Signaling in AgRP Neurons Reduces Food Intake and Improves Systemic Insulin Sensitivity in Obesity Cell Reports obesity insulin sensitivity AgRP neurons P2Y6 diabetes food intake hypothalamus arcuate nucleus insulin resistance |
| title | Inhibition of P2Y6 Signaling in AgRP Neurons Reduces Food Intake and Improves Systemic Insulin Sensitivity in Obesity |
| title_full | Inhibition of P2Y6 Signaling in AgRP Neurons Reduces Food Intake and Improves Systemic Insulin Sensitivity in Obesity |
| title_fullStr | Inhibition of P2Y6 Signaling in AgRP Neurons Reduces Food Intake and Improves Systemic Insulin Sensitivity in Obesity |
| title_full_unstemmed | Inhibition of P2Y6 Signaling in AgRP Neurons Reduces Food Intake and Improves Systemic Insulin Sensitivity in Obesity |
| title_short | Inhibition of P2Y6 Signaling in AgRP Neurons Reduces Food Intake and Improves Systemic Insulin Sensitivity in Obesity |
| title_sort | inhibition of p2y6 signaling in agrp neurons reduces food intake and improves systemic insulin sensitivity in obesity |
| topic | obesity insulin sensitivity AgRP neurons P2Y6 diabetes food intake hypothalamus arcuate nucleus insulin resistance |
| url | http://www.sciencedirect.com/science/article/pii/S221112471730102X |
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