Home > Publications Database > Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity. > print

001     154267
005     20240529143839.0
024 7 _ |a 10.1172/JCI136363
|2 doi
024 7 _ |a pmid:32780722
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024 7 _ |a pmc:PMC7598066
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024 7 _ |a 0021-9738
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024 7 _ |a 1558-8238
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037 _ _ |a DZNE-2021-00121
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Schriever, Sonja C
|b 0
245 _ _ |a Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity.
260 _ _ |a Ann Arbor, Mich.
|c 2020
|b ASCJ
336 7 _ |a article
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336 7 _ |a Journal Article
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336 7 _ |a Journal Article
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500 _ _ |a ISSN 1558-8238 not unique: **3 hits**.
520 _ _ |a 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.
536 _ _ |a 342 - Disease Mechanisms and Model Systems (POF3-342)
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588 _ _ |a Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de
650 _ 7 |a Diabetes
|2 Other
650 _ 7 |a Metabolism
|2 Other
650 _ 7 |a Obesity
|2 Other
650 _ 7 |a MAP Kinase Kinase 4
|0 EC 2.7.12.2
|2 NLM Chemicals
650 _ 7 |a DUSP8 protein, mouse
|0 EC 3.1.3.16
|2 NLM Chemicals
650 _ 7 |a Dual-Specificity Phosphatases
|0 EC 3.1.3.48
|2 NLM Chemicals
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Diabetes Mellitus, Experimental: enzymology
|2 MeSH
650 _ 2 |a Diabetes Mellitus, Experimental: genetics
|2 MeSH
650 _ 2 |a Diabetes Mellitus, Type 2: enzymology
|2 MeSH
650 _ 2 |a Diabetes Mellitus, Type 2: genetics
|2 MeSH
650 _ 2 |a Dual-Specificity Phosphatases: genetics
|2 MeSH
650 _ 2 |a Dual-Specificity Phosphatases: metabolism
|2 MeSH
650 _ 2 |a Hypothalamus: enzymology
|2 MeSH
650 _ 2 |a Insulin Resistance
|2 MeSH
650 _ 2 |a MAP Kinase Kinase 4: genetics
|2 MeSH
650 _ 2 |a MAP Kinase Kinase 4: metabolism
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Mice, Knockout
|2 MeSH
650 _ 2 |a Signal Transduction
|2 MeSH
700 1 _ |a Kabra, Dhiraj G
|b 1
700 1 _ |a Pfuhlmann, Katrin
|b 2
700 1 _ |a Baumann, Peter
|b 3
700 1 _ |a Baumgart, Emily V
|b 4
700 1 _ |a Nagler, Joachim
|b 5
700 1 _ |a Seebacher, Fabian
|b 6
700 1 _ |a Harrison, Luke
|b 7
700 1 _ |a Irmler, Martin
|b 8
700 1 _ |a Kullmann, Stephanie
|b 9
700 1 _ |a Corrêa-da-Silva, Felipe
|b 10
700 1 _ |a Giesert, Florian
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700 1 _ |a Jain, Ruchi
|b 12
700 1 _ |a Schug, Hannah
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700 1 _ |a Castel, Julien
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700 1 _ |a Martinez, Sarah
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700 1 _ |a Wu, Moya
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700 1 _ |a Häring, Hans-Ulrich
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700 1 _ |a de Angelis, Martin Hrabe
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700 1 _ |a Beckers, Johannes
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700 1 _ |a Müller, Timo D
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700 1 _ |a Stemmer, Kerstin
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700 1 _ |a Wurst, Wolfgang
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700 1 _ |a Rozman, Jan
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700 1 _ |a Nogueiras, Ruben
|b 24
700 1 _ |a De Angelis, Meri
|b 25
700 1 _ |a Molkentin, Jeffery D
|b 26
700 1 _ |a Krahmer, Natalie
|b 27
700 1 _ |a Yi, Chun-Xia
|b 28
700 1 _ |a Schmidt, Mathias V
|b 29
700 1 _ |a Luquet, Serge
|b 30
700 1 _ |a Heni, Martin
|b 31
700 1 _ |a Tschöp, Matthias H
|b 32
700 1 _ |a Pfluger, Paul T
|b 33
773 _ _ |a 10.1172/JCI136363
|g Vol. 130, no. 11, p. 6093 - 6108
|0 PERI:(DE-600)2018375-6
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|p 6093 - 6108
|t The journal of clinical investigation
|v 130
|y 2020
|x 1558-8238
856 4 _ |u https://www.jci.org/articles/view/136363
856 4 _ |u https://pub.dzne.de/record/154267/files/DZNE-2021-00121_Restricted.pdf
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