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.

Biological Research Pharmacology Department Sun Pharma Advanced Research Company Ltd Vadodara India

Chair of Experimental Genetics School of Life Sciences Weihenstephan Technical University of Munich Freising Germany

Czech Centre for Phenogenomics Institute of Molecular Genetics of the Czech Academy of Sciences Vestec Czech Republic

Department of Developmental Genetics School of Life Sciences Weihenstephan Technical University of Munich Munich Germany

Department of Endocrinology and Metabolism Amsterdam University Medical Center University of Amsterdam Amsterdam Netherlands

Department of Pediatrics University of Cincinnati Cincinnati Ohio USA

Department of Physiology Instituto de Investigación Sanitaria University of Santiago de Compostela Santiago de Compostela Spain

Division of Endocrinology Diabetology and Nephrology Department of Internal Medicine 4 University of Tübingen Tübingen Germany

Division of Metabolic Diseases and

German Center for Diabetes Research Neuherberg Germany

German Center for Neurodegenerative Diseases Munich Germany

Howard Hughes Medical Institute Cincinnati Children's Hospital Medical Center Cincinnati Ohio USA

Institute for Clinical Chemistry and Pathobiochemistry Department for Diagnostic Laboratory Medicine University Hospital Tübingen Tübingen Germany

Institute for Diabetes and Obesity Helmholtz Zentrum München Neuherberg Germany

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen Tübingen Germany

Institute of Developmental Genetics Helmholtz Zentrum München Neuherberg Germany

Institute of Experimental and Clinical Pharmacology and Toxicology Department of Pharmacology and Experimental Therapy Eberhard Karls University Hospitals and Clinics Tübingen Germany

Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München Neuherberg Germany

Lund University Diabetes Centre Clinical Research Centre Skåne University Hospital Malmö Malmö Sweden

Molecular EXposomics and

Munich Cluster for Systems Neurology Munich Germany

Netherlands Institute for Neuroscience an Institute of the Royal Netherlands Academy of Arts and Sciences Amsterdam Netherlands

Neurobiology of Diabetes School of Medicine Technical University of Munich Munich Germany

Neurobiology of Stress Resilience Max Planck Institute of Psychiatry Munich Germany

Research Unit NeuroBiology of Diabetes and

SYNLAB Analytics and Services Switzerland AG Dielsdorf Switzerland

Université de Paris BFA UMR 8251 CNRS Paris France

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J Diabetes Investig. 2021 Jul;12(7):1138-1140. doi: 10.1111/jdi.13561. PubMed

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