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Schriever, S.C. ; Kabra, D.G. ; Pfuhlmann, K. ; Baumann, P. ; Baumgart, E.V. ; Nagler, J. ; Seebacher, F. ; Harrison, L. ; Irmler, M. ; Kullmann, S. ; Corrêa-da-Silva, F.* ; Giesert, F. ; Jain, R.* ; Schug, H.* ; Castel, J.* ; Martinez, S.* ; Wu, M. ; Häring, H.-U. ; Hrabě de Angelis, M. ; Beckers, J. ; Müller, T.D. ; Stemmer, K. ; Wurst, W. ; Rozman, J. ; Nogueiras, R.* ; de Angelis, M. ; Molkentin, J.D.* ; Krahmer, N. ; Yi, C.-X.* ; Schmidt, M.V.* ; Luquet, S.* ; Heni, M. ; Tschöp, M.H. ; Pfluger, P.T.

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

J. Clin. Invest. 130, 6093-6108 (2020)
Publ. Version/Full Text Postprint DOI PMC
Open Access Green
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Diabetes; Metabolism; Obesity; Glucocorticoid-receptor; Resistance; Glucose; Obesity; Inflammation; Association; Expression; Stress; Brain; Responsiveness
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Journal Journal of Clinical Investigation
Quellenangaben Volume: 130, Issue: 11, Pages: 6093-6108 Article Number: , Supplement: ,
Publisher American Society of Clinical Investigation
Publishing Place 2015 Manchester Rd, Ann Arbor, Mi 48104 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
PPM-MEX-Molecular EXposomics (MEX)
Institute of Experimental Genetics (IEG)
Institute of Diabetes Research and Metabolic Diseases (IDM)
Institute of Developmental Genetics (IDG)
Grants Initiative and Networking Fund of the Helmholtz Association
Alexander von Humboldt Foundation
Helmholtz Alliance ICEMED-Imaging and Curing Environmental Metabolic Diseases
German Center for Diabetes Research
Helmholtz-Israel Cooperation in Personalized Medicine
Helmholtz Initiative for Personalized Medicine (iMed)
Helmholtz Alliance Aging and Metabolic Programming, AMPro
Emmy-Noether DFG
German Federal Ministry of Education and Research
Helmholtz Portfolio Program Metabolic Dysfunction