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Autor
Baumann, Peter 1 Baumgart, Emily V 1 Beckers, Johannes 1 Castel, Julien 1 Corrêa-da-Silva, Felipe 1 De Angelis, Meri 1 Giesert, Florian 1 Harrison, Luke 1 Heni, Martin 1 Häring, Hans-Ulrich 1 Irmler, Martin 1 Jain, Ruchi 1 Kabra, Dhiraj G 1 Krahmer, Natalie 1 Kullmann, Stephanie 1 Luquet, Serge 1 Martinez, Sarah 1 Molkentin, Jeffery D 1 Müller, Timo D 1 Nagler, Joachim 1
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Pracoviště
Biological Research Pharmacology Depa... 1 Chair of Experimental Genetics School... 1 Czech Centre for Phenogenomics Instit... 1 Department of Developmental Genetics ... 1 Department of Endocrinology and Metab... 1 Department of Pediatrics University o... 1 Department of Physiology Instituto de... 1 Division of Endocrinology Diabetology... 1 Division of Metabolic Diseases and 1 German Center for Diabetes Research N... 1 German Center for Neurodegenerative D... 1 Howard Hughes Medical Institute Cinci... 1 Institute for Clinical Chemistry and ... 1 Institute for Diabetes Research and M... 1 Institute for Diabetes and Obesity He... 1 Institute of Developmental Genetics H... 1 Institute of Experimental Genetics an... 1 Institute of Experimental and Clinica... 1 Lund University Diabetes Centre Clini... 1 Molecular EXposomics and 1
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Autor
Baumann, Peter 1 Baumgart, Emily V 1 Beckers, Johannes 1 Castel, Julien 1 Corrêa-da-Silva, Felipe 1 De Angelis, Meri 1 Giesert, Florian 1 Harrison, Luke 1 Heni, Martin 1 Häring, Hans-Ulrich 1 Irmler, Martin 1 Jain, Ruchi 1 Kabra, Dhiraj G 1 Krahmer, Natalie 1 Kullmann, Stephanie 1 Luquet, Serge 1 Martinez, Sarah 1 Molkentin, Jeffery D 1 Müller, Timo D 1 Nagler, Joachim 1
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Pracoviště
Biological Research Pharmacology Depa... 1 Chair of Experimental Genetics School... 1 Czech Centre for Phenogenomics Instit... 1 Department of Developmental Genetics ... 1 Department of Endocrinology and Metab... 1 Department of Pediatrics University o... 1 Department of Physiology Instituto de... 1 Division of Endocrinology Diabetology... 1 Division of Metabolic Diseases and 1 German Center for Diabetes Research N... 1 German Center for Neurodegenerative D... 1 Howard Hughes Medical Institute Cinci... 1 Institute for Clinical Chemistry and ... 1 Institute for Diabetes Research and M... 1 Institute for Diabetes and Obesity He... 1 Institute of Developmental Genetics H... 1 Institute of Experimental Genetics an... 1 Institute of Experimental and Clinica... 1 Lund University Diabetes Centre Clini... 1 Molecular EXposomics and 1
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- Schriever, Sonja C
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Kabra, Dhiraj G
Autor Kabra, Dhiraj G Research Unit NeuroBiology of Diabetes and Institute for Diabetes and Obesity, Helmholtz Zentrum München, Neuherberg, Germany German Center for Diabetes Research (DZD), Neuherberg, Germany Biological Research Pharmacology Department, Sun Pharma Advanced Research Company Ltd., Vadodara, India
- Pfuhlmann, Katrin
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Baumann, Peter
Autor Baumann, Peter Research Unit NeuroBiology of Diabetes and Institute for Diabetes and Obesity, Helmholtz Zentrum München, Neuherberg, Germany German Center for Diabetes Research (DZD), Neuherberg, Germany Neurobiology of Diabetes, School of Medicine, Technical University of Munich, Munich, Germany
- Baumgart, Emily V
- Nagler, Joachim
- Seebacher, Fabian
- Harrison, Luke
- Irmler, Martin
- Kullmann, Stephanie
Freely Accessible Science Journals od 1924 do Před 1 rokem
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Europe PubMed Central od 1924 do Před 1 rokem
ProQuest Central od 2002-07-01
Open Access Digital Library od 1924-10-01
Open Access Digital Library od 1925-08-01
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Health & Medicine (ProQuest) od 2002-07-01
PubMed
32780722
DOI
10.1172/jci136363
Knihovny.cz E-zdroje
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.
- MeSH
- diabetes mellitus 2. typu enzymologie genetika MeSH
- experimentální diabetes mellitus enzymologie genetika MeSH
- fosfatasy s dvojí specifitou genetika metabolismus MeSH
- hypothalamus enzymologie MeSH
- inzulinová rezistence * MeSH
- MAP kinasa-kinasa 4 genetika metabolismus MeSH
- myši knockoutované MeSH
- myši MeSH
- signální transdukce * MeSH
- zvířata MeSH
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- časopisecké články MeSH
- práce podpořená grantem MeSH
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