Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity
Authors: Florian Giesert
Matthias H Tschöp
Kerstin Stemmer
Katrin Pfuhlmann
Hannah Schug
Chun-Xia Yi
Ruben Nogueiras
Moya Wu
Jan Rozman
Paul T Pfluger
Meri De Angelis
Ruchi Jain
Dhiraj G Kabra
Martin Hrabe de Angelis
Johannes Beckers
Natalie Krahmer
Martin Heni
Timo D Müller
Jeffery D Molkentin
Fabian Seebacher
Peter Baumann
Mathias V Schmidt
Wolfgang Wurst
Felipe Corrêa-da-Silva
Sonja C Schriever
Martin Irmler
Julien Castel
Luke Harrison
Hans-Ulrich Häring
Stephanie Kullmann
Emily V Baumgart
Joachim Nagler
Serge Luquet
Sarah Martinez
Journal: Journal of Clinical Investigation (2020)
Discipline: CLINICAL MEDICINE
Keywords: Diabetes; Metabolism; Obesity.
Affiliations: NeuroBiology of Diabetes, Helmholtz Centre Munich, Munich, Germany., Institute for Diabetes and Obesity, Helmholtz Centre Munich, Munich, Germany., Molecular EXposomics, Helmholtz Centre Munich, Munich, Germany., Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Centre Munich, Munich, Germany., Institute for Diabetes Research and Metabolic Diseases, University of Tübingen, Tübingen, Germany., Department of Endocrinology and Metabolism, University of Amsterdam, Amsterdam, Netherlands., Institute of Developmental Genetics, Helmholtz Centre Munich, Munich, Germany., Lund University Diabetes Centre, Lund University, Malmö, Sweden., Analytics & Services, SYNLAB Analytics & Services Switzerland AG, Dielsdorf, Switzerland., EAC 4413 CNRS, Université de Paris, Paris, France., Unit of Functional and Adaptive Biology, Université de Paris, Paris, France., Institute of Experimental Genetics, Helmholtz Centre Munich, Munich, Germany., Czech Centre for Phenogenomics, Czech Academy of Sciences, Prague, Czech Republic., Department of Physiology, University of Santiago de Compostela, Santiago de Compostela, Spain., Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America., Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany., Unit of Functional and Adaptive Biology (BFA), Université de Paris, Paris, France., Division of Endocrinology, Diabetology and Nephrology, University of Tübingen, Tuebingen, Germany.

Abstract:  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. 

Retracted: No

PubPeer comments:
 What volume of AAV was injected into the hypothalamus? Thanks. ,