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@ARTICLE{Schriever:154267,
      author       = {Schriever, Sonja C and Kabra, Dhiraj G and Pfuhlmann,
                      Katrin and Baumann, Peter and Baumgart, Emily V and Nagler,
                      Joachim and Seebacher, Fabian and Harrison, Luke and Irmler,
                      Martin and Kullmann, Stephanie and Corrêa-da-Silva, Felipe
                      and Giesert, Florian and Jain, Ruchi and Schug, Hannah and
                      Castel, Julien and Martinez, Sarah and Wu, Moya and Häring,
                      Hans-Ulrich and de Angelis, Martin Hrabe and Beckers,
                      Johannes and Müller, Timo D and Stemmer, Kerstin and Wurst,
                      Wolfgang and Rozman, Jan and Nogueiras, Ruben and De
                      Angelis, Meri and Molkentin, Jeffery D and Krahmer, Natalie
                      and Yi, Chun-Xia and Schmidt, Mathias V and Luquet, Serge
                      and Heni, Martin and Tschöp, Matthias H and Pfluger, Paul
                      T},
      title        = {{T}ype 2 diabetes risk gene {D}usp8 regulates hypothalamic
                      {J}nk signaling and insulin sensitivity.},
      journal      = {The journal of clinical investigation},
      volume       = {130},
      number       = {11},
      issn         = {1558-8238},
      address      = {Ann Arbor, Mich.},
      publisher    = {ASCJ},
      reportid     = {DZNE-2021-00121},
      pages        = {6093 - 6108},
      year         = {2020},
      note         = {ISSN 1558-8238 not unique: **3 hits**.},
      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.},
      keywords     = {Animals / Diabetes Mellitus, Experimental: enzymology /
                      Diabetes Mellitus, Experimental: genetics / Diabetes
                      Mellitus, Type 2: enzymology / Diabetes Mellitus, Type 2:
                      genetics / Dual-Specificity Phosphatases: genetics /
                      Dual-Specificity Phosphatases: metabolism / Hypothalamus:
                      enzymology / Insulin Resistance / MAP Kinase Kinase 4:
                      genetics / MAP Kinase Kinase 4: metabolism / Mice / Mice,
                      Knockout / Signal Transduction / Diabetes (Other) /
                      Metabolism (Other) / Obesity (Other) / MAP Kinase Kinase 4
                      (NLM Chemicals) / DUSP8 protein, mouse (NLM Chemicals) /
                      Dual-Specificity Phosphatases (NLM Chemicals)},
      cin          = {München common / AG Wurst},
      ddc          = {610},
      cid          = {I:(DE-2719)6000016 / I:(DE-2719)1140001},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:32780722},
      pmc          = {pmc:PMC7598066},
      doi          = {10.1172/JCI136363},
      url          = {https://pub.dzne.de/record/154267},
}