Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity

Autor: 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
Přispěvatelé: 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, Amsterdam Gastroenterology Endocrinology Metabolism
Jazyk: angličtina
Rok vydání: 2020
Předmět:
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
Zdroj: The Journal of clinical investigation
The Journal of clinical investigation, 2020, 130 (11), pp.6093-6108. ⟨10.1172/JCI136363⟩
The journal of clinical investigation 130(11), 6093-6108 (2020). doi:10.1172/JCI136363
The journal of clinical investigation, 130(11), 6093-6108. The American Society for Clinical Investigation
Journal of Diabetes Investigation
J. Clin. Invest. 130, 6093-6108 (2020)
Journal of clinical investigation, 130(11), 6093-6108. The American Society for Clinical Investigation
ISSN: 1558-8238
0021-9738
Popis: 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.
Databáze: OpenAIRE
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