1. Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity
- Author
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Florian Giesert, Dhiraj G. Kabra, Timo D. Müller, Kerstin Stemmer, Meri De Angelis, Martin Hrabé de Angelis, Fabian Seebacher, Martin Heni, Sonja C. Schriever, Ruchi Jain, Luke Harrison, Moya Wu, Martin Irmler, Rubén Nogueiras, Johannes Beckers, Hans-Ulrich Häring, Serge Luquet, Stephanie Kullmann, Chun-Xia Yi, Natalie Krahmer, Felipe Correa-da-Silva, Emily Violette Baumgart, Julien Castel, Paul T. Pfluger, Sarah Martinez, Peter Baumann, Mathias V. Schmidt, Jeffery D. Molkentin, Katrin Pfuhlmann, Hannah Schug, Jan Rozman, Wolfgang Wurst, Joachim Nagler, Matthias H. Tschöp, Helmholtz-Zentrum München (HZM), German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Institute for Diabetes Research and Metabolic Diseases [Tübingen, Germany], VU University Medical Center [Amsterdam], Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), TUM School of Life Sciences Weihenstephan, Skane University Hospital [Malmo], Lund University [Lund], Synlab [Lausanne], Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), School Life Science Weihenstephan (TUM), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), Institute of Molecular Genetics of the Czech Academy of Sciences (IMG / CAS), Czech Academy of Sciences [Prague] (CAS), Howard Hughes Medical Institute (HHMI), Cincinnati Children's Hospital Medical Center, Institute of the Royal Netherlands Academy of Arts and Sciences, Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Endocrinology, Laboratory for Endocrinology, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, and Amsterdam Gastroenterology Endocrinology Metabolism
- Subjects
0301 basic medicine ,MAP Kinase Kinase 4 ,[SDV]Life Sciences [q-bio] ,Type 2 diabetes ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Corticosterone ,enzymology [Hypothalamus] ,Glucose homeostasis ,genetics [Diabetes Mellitus, Experimental] ,Mice, Knockout ,Kinase ,Diabetes ,enzymology [Diabetes Mellitus, Experimental] ,General Medicine ,metabolism [Dual-Specificity Phosphatases] ,DUSP8 protein, mouse ,030220 oncology & carcinogenesis ,Dual-Specificity Phosphatases ,medicine.symptom ,Signal Transduction ,medicine.medical_specialty ,Hypothalamus ,enzymology [Diabetes Mellitus, Type 2] ,Inflammation ,genetics [Diabetes Mellitus, Type 2] ,Diabetes Mellitus, Experimental ,03 medical and health sciences ,Insulin resistance ,Commentaries ,Internal medicine ,Diabetes mellitus ,medicine ,Animals ,genetics [MAP Kinase Kinase 4] ,ddc:610 ,Obesity ,genetics [Dual-Specificity Phosphatases] ,business.industry ,metabolism [MAP Kinase Kinase 4] ,medicine.disease ,030104 developmental biology ,Endocrinology ,Metabolism ,Diabetes Mellitus, Type 2 ,chemistry ,Commentary ,Insulin Resistance ,business ,Hormone - Abstract
International audience; Recent genome-wide association studies (GWAS) identified DUSP8, encoding a dual-specificity phosphatase targeting mitogen-activated protein kinases, as a type 2 diabetes (T2D) risk gene. Here, we reveal that Dusp8 is a gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male, but not female, Dusp8 loss-of-function mice, either with global or corticotropin-releasing hormone neuron-specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD). Mechanistically, we found impaired hypothalamic-pituitary-adrenal axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling. Accordingly, global Jnk1 ablation, AAV-mediated Dusp8 overexpression in the mediobasal hypothalamus, or metyrapone-induced chemical adrenalectomy rescued the impaired glucose homeostasis of obese male Dusp8-KO mice, respectively. The sex-specific role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity, and systemic glucose tolerance was consistent with functional MRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men. Further, expression of DUSP8 was increased in the infundibular nucleus of T2D humans. In summary, our findings suggest the GWAS-identified gene Dusp8 as a novel hypothalamic factor that plays a functional role in the etiology of T2D.
- Published
- 2020