Peter Baumann1,2,3,4, Sonja C Schriever1,2,3, Stephanie Kullmann3,5,6, Annemarie Zimprich7,8,9, Andreas Peter3,5,10, Valerie Gailus-Durner7, Helmut Fuchs7, Martin Hrabe de Angelis3,7,11, Wolfgang Wurst8,9,12,13, Matthias H Tschöp2,3,14, Martin Heni3,5,6,10, Sabine M Hölter7,8,9, Paul T Pfluger1,2,3,4. 1. Research Unit Neurobiology of Diabetes, Helmholtz Zentrum München, Neuherberg, Germany. 2. Institute for Diabetes and Obesity, Helmholtz Zentrum München, Neuherberg, Germany. 3. German Center for Diabetes Research (DZD), Neuherberg, Germany. 4. Neurobiology of Diabetes, TUM School of Medicine, Technical University of Munich, Munich, Germany. 5. Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany. 6. Department of Internal Medicine IV, University Hospital of Tübingen, Tübingen, Germany. 7. German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany. 8. Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany. 9. Chair of Developmental Genetics, c/o Helmholtz Zentrum München, Technische Universität München-Weihenstephan, Neuherberg, Germany. 10. Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital of Tübingen, Tübingen, Germany. 11. Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising, Germany. 12. German Center for Neurodegenerative Diseases (DZNE) Site Munich, Munich, Germany. 13. Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-Universität München, Munich, Germany. 14. Division of Metabolic Diseases, Technische Universität München, Munich, Germany.
Abstract
BACKGROUND: Dusp8 is the first GWAS-identified gene that is predominantly expressed in the brain and has previously been linked with the development of diabetes type 2 in humans. In this study, we unravel how Dusp8 is involved in the regulation of sucrose reward behavior. METHODS: Female, chow-fed global Dusp8 WT and KO mice were tested in an observer-independent IntelliCage setup for self-administrative sucrose consumption and preference followed by a progressive ratio task with restricted sucrose access to monitor seeking and motivation behavior. Sixty-three human carriers of the major C and minor T allele of DUSP8 SNP rs2334499 were tested for their perception of food cues by collecting a rating score for sweet versus savory high caloric food. RESULTS: Dusp8 KO mice showed a comparable preference for sucrose, but consumed more sucrose compared to WT mice. In a progressive ratio task, Dusp8 KO females switched to a "trial and error" strategy to find sucrose while control Dusp8 WT mice kept their previously established seeking pattern. Nonetheless, the overall motivation to consume sucrose, and the levels of dopaminergic neurons in the brain areas NAcc and VTA were comparable between genotypes. Diabetes-risk allele carriers of DUSP8 SNP rs2334499 preferred sweet high caloric food compared to the major allele carriers, rating scores for savory food remained comparable between groups. CONCLUSION: Our data suggest a novel role for Dusp8 in the perception of sweet high caloric food as well as in the control of sucrose consumption and foraging in mice and humans.
BACKGROUND: Dusp8 is the first GWAS-identified gene that is predominantly expressed in the brain and has previously been linked with the development of diabetes type 2 in humans. In this study, we unravel how Dusp8 is involved in the regulation of sucrose reward behavior. METHODS: Female, chow-fed global Dusp8 WT and KO mice were tested in an observer-independent IntelliCage setup for self-administrative sucrose consumption and preference followed by a progressive ratio task with restricted sucrose access to monitor seeking and motivation behavior. Sixty-three human carriers of the major C and minor T allele of DUSP8 SNP rs2334499 were tested for their perception of food cues by collecting a rating score for sweet versus savory high caloric food. RESULTS: Dusp8 KO mice showed a comparable preference for sucrose, but consumed more sucrose compared to WT mice. In a progressive ratio task, Dusp8 KO females switched to a "trial and error" strategy to find sucrose while control Dusp8 WT mice kept their previously established seeking pattern. Nonetheless, the overall motivation to consume sucrose, and the levels of dopaminergic neurons in the brain areas NAcc and VTA were comparable between genotypes. Diabetes-risk allele carriers of DUSP8 SNP rs2334499 preferred sweet high caloric food compared to the major allele carriers, rating scores for savory food remained comparable between groups. CONCLUSION: Our data suggest a novel role for Dusp8 in the perception of sweet high caloric food as well as in the control of sucrose consumption and foraging in mice and humans.
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