TY  - JOUR
AU  - Schriever, Sonja C
AU  - Kabra, Dhiraj G
AU  - Pfuhlmann, Katrin
AU  - Baumann, Peter
AU  - Baumgart, Emily V
AU  - Nagler, Joachim
AU  - Seebacher, Fabian
AU  - Harrison, Luke
AU  - Irmler, Martin
AU  - Kullmann, Stephanie
AU  - Corrêa-da-Silva, Felipe
AU  - Giesert, Florian
AU  - Jain, Ruchi
AU  - Schug, Hannah
AU  - Castel, Julien
AU  - Martinez, Sarah
AU  - Wu, Moya
AU  - Häring, Hans-Ulrich
AU  - de Angelis, Martin Hrabe
AU  - Beckers, Johannes
AU  - Müller, Timo D
AU  - Stemmer, Kerstin
AU  - Wurst, Wolfgang
AU  - Rozman, Jan
AU  - Nogueiras, Ruben
AU  - De Angelis, Meri
AU  - Molkentin, Jeffery D
AU  - Krahmer, Natalie
AU  - Yi, Chun-Xia
AU  - Schmidt, Mathias V
AU  - Luquet, Serge
AU  - Heni, Martin
AU  - Tschöp, Matthias H
AU  - Pfluger, Paul T
TI  - Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity.
JO  - The journal of clinical investigation
VL  - 130
IS  - 11
SN  - 1558-8238
CY  - Ann Arbor, Mich.
PB  - ASCJ
M1  - DZNE-2021-00121
SP  - 6093 - 6108
PY  - 2020
N1  - ISSN 1558-8238 not unique: **3 hits**.
AB  - 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.
KW  - Animals
KW  - Diabetes Mellitus, Experimental: enzymology
KW  - Diabetes Mellitus, Experimental: genetics
KW  - Diabetes Mellitus, Type 2: enzymology
KW  - Diabetes Mellitus, Type 2: genetics
KW  - Dual-Specificity Phosphatases: genetics
KW  - Dual-Specificity Phosphatases: metabolism
KW  - Hypothalamus: enzymology
KW  - Insulin Resistance
KW  - MAP Kinase Kinase 4: genetics
KW  - MAP Kinase Kinase 4: metabolism
KW  - Mice
KW  - Mice, Knockout
KW  - Signal Transduction
KW  - Diabetes (Other)
KW  - Metabolism (Other)
KW  - Obesity (Other)
KW  - MAP Kinase Kinase 4 (NLM Chemicals)
KW  - DUSP8 protein, mouse (NLM Chemicals)
KW  - Dual-Specificity Phosphatases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:32780722
C2  - pmc:PMC7598066
DO  - DOI:10.1172/JCI136363
UR  - https://pub.dzne.de/record/154267
ER  -