The Fat Mass and Obesity-Associated Protein (FTO) Regulates Locomotor Responses to Novelty via D2R Medium Spiny Neurons
Summary: Variations in the human FTO gene have been linked to obesity and altered connectivity of the dopaminergic neurocircuitry. Here, we report that fat mass and obesity-associated protein (FTO) in dopamine D2 receptor-expressing medium spiny neurons (D2 MSNs) of mice regulate the excitability of...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-06-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719306576 |
| _version_ | 1811201491938050048 |
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| author | Johan Ruud Jens Alber Anna Tokarska Linda Engström Ruud Hendrik Nolte Nasim Biglari Rachel Lippert Änne Lautenschlager Przemysław E. Cieślak Łukasz Szumiec Martin E. Hess Hella S. Brönneke Marcus Krüger Hans Nissbrandt Tatiana Korotkova Gilad Silberberg Jan Rodriguez Parkitna Jens C. Brüning |
| author_facet | Johan Ruud Jens Alber Anna Tokarska Linda Engström Ruud Hendrik Nolte Nasim Biglari Rachel Lippert Änne Lautenschlager Przemysław E. Cieślak Łukasz Szumiec Martin E. Hess Hella S. Brönneke Marcus Krüger Hans Nissbrandt Tatiana Korotkova Gilad Silberberg Jan Rodriguez Parkitna Jens C. Brüning |
| author_sort | Johan Ruud |
| collection | DOAJ |
| description | Summary: Variations in the human FTO gene have been linked to obesity and altered connectivity of the dopaminergic neurocircuitry. Here, we report that fat mass and obesity-associated protein (FTO) in dopamine D2 receptor-expressing medium spiny neurons (D2 MSNs) of mice regulate the excitability of these cells and control their striatopallidal globus pallidus external (GPe) projections. Lack of FTO in D2 MSNs translates into increased locomotor activity to novelty, associated with altered timing behavior, without impairing the ability to control actions or affecting reward-driven and conditioned behavior. Pharmacological manipulations of dopamine D1 receptor (D1R)- or D2R-dependent pathways in these animals reveal altered responses to D1- and D2-MSN-mediated control of motor output. These findings reveal a critical role for FTO to control D2 MSN excitability, their projections to the GPe, and behavioral responses to novelty. : Ruud et al. find that FTO, an obesity-risk gene, regulates physical activity via dopamine D2 receptor-expressing medium spiny neurons in the brain. Although FTO regulates the firing of and limits locomotion through those neurons, these changes do not predispose mice to weight gain or altered food reward. |
| first_indexed | 2024-04-12T02:22:33Z |
| format | Article |
| id | doaj.art-a536d8e99e444152a3de8a1661f87a00 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-12T02:22:33Z |
| publishDate | 2019-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-a536d8e99e444152a3de8a1661f87a002022-12-22T03:52:05ZengElsevierCell Reports2211-12472019-06-01271131823198.e9The Fat Mass and Obesity-Associated Protein (FTO) Regulates Locomotor Responses to Novelty via D2R Medium Spiny NeuronsJohan Ruud0Jens Alber1Anna Tokarska2Linda Engström Ruud3Hendrik Nolte4Nasim Biglari5Rachel Lippert6Änne Lautenschlager7Przemysław E. Cieślak8Łukasz Szumiec9Martin E. Hess10Hella S. Brönneke11Marcus Krüger12Hans Nissbrandt13Tatiana Korotkova14Gilad Silberberg15Jan Rodriguez Parkitna16Jens C. Brüning17Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for 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, Germany; Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, GermanyDepartment of Neuroscience, Karolinska Institutet, Stockholm 17177, SwedenDepartment of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for 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 for 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, Germany; Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for 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, Germany; Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for 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, Germany; Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, GermanyDepartment of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Krakow, PolandDepartment of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Krakow, PolandDepartment of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for 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, Germany; Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for 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 for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, GermanyDepartment of Pharmacology, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, 40530 Gothenburg, SwedenDepartment of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, GermanyDepartment of Neuroscience, Karolinska Institutet, Stockholm 17177, SwedenDepartment of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Krakow, PolandDepartment of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for 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; Corresponding authorSummary: Variations in the human FTO gene have been linked to obesity and altered connectivity of the dopaminergic neurocircuitry. Here, we report that fat mass and obesity-associated protein (FTO) in dopamine D2 receptor-expressing medium spiny neurons (D2 MSNs) of mice regulate the excitability of these cells and control their striatopallidal globus pallidus external (GPe) projections. Lack of FTO in D2 MSNs translates into increased locomotor activity to novelty, associated with altered timing behavior, without impairing the ability to control actions or affecting reward-driven and conditioned behavior. Pharmacological manipulations of dopamine D1 receptor (D1R)- or D2R-dependent pathways in these animals reveal altered responses to D1- and D2-MSN-mediated control of motor output. These findings reveal a critical role for FTO to control D2 MSN excitability, their projections to the GPe, and behavioral responses to novelty. : Ruud et al. find that FTO, an obesity-risk gene, regulates physical activity via dopamine D2 receptor-expressing medium spiny neurons in the brain. Although FTO regulates the firing of and limits locomotion through those neurons, these changes do not predispose mice to weight gain or altered food reward.http://www.sciencedirect.com/science/article/pii/S2211124719306576 |
| spellingShingle | Johan Ruud Jens Alber Anna Tokarska Linda Engström Ruud Hendrik Nolte Nasim Biglari Rachel Lippert Änne Lautenschlager Przemysław E. Cieślak Łukasz Szumiec Martin E. Hess Hella S. Brönneke Marcus Krüger Hans Nissbrandt Tatiana Korotkova Gilad Silberberg Jan Rodriguez Parkitna Jens C. Brüning The Fat Mass and Obesity-Associated Protein (FTO) Regulates Locomotor Responses to Novelty via D2R Medium Spiny Neurons Cell Reports |
| title | The Fat Mass and Obesity-Associated Protein (FTO) Regulates Locomotor Responses to Novelty via D2R Medium Spiny Neurons |
| title_full | The Fat Mass and Obesity-Associated Protein (FTO) Regulates Locomotor Responses to Novelty via D2R Medium Spiny Neurons |
| title_fullStr | The Fat Mass and Obesity-Associated Protein (FTO) Regulates Locomotor Responses to Novelty via D2R Medium Spiny Neurons |
| title_full_unstemmed | The Fat Mass and Obesity-Associated Protein (FTO) Regulates Locomotor Responses to Novelty via D2R Medium Spiny Neurons |
| title_short | The Fat Mass and Obesity-Associated Protein (FTO) Regulates Locomotor Responses to Novelty via D2R Medium Spiny Neurons |
| title_sort | fat mass and obesity associated protein fto regulates locomotor responses to novelty via d2r medium spiny neurons |
| url | http://www.sciencedirect.com/science/article/pii/S2211124719306576 |
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