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Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity
Sonja C. Schriever, … , Matthias H. Tschöp, Paul T. Pfluger
Sonja C. Schriever, … , Matthias H. Tschöp, Paul T. Pfluger
Published August 11, 2020
Citation Information: J Clin Invest. 2020;130(11):6093-6108. https://doi.org/10.1172/JCI136363.
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Research Article Metabolism Article has an altmetric score of 87

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

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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.

Authors

Sonja C. Schriever, Dhiraj G. Kabra, Katrin Pfuhlmann, Peter Baumann, Emily V. Baumgart, Joachim Nagler, Fabian Seebacher, Luke Harrison, Martin Irmler, Stephanie Kullmann, Felipe Corrêa-da-Silva, Florian Giesert, Ruchi Jain, Hannah Schug, Julien Castel, Sarah Martinez, Moya Wu, Hans-Ulrich Häring, Martin Hrabe de Angelis, Johannes Beckers, Timo D. Müller, Kerstin Stemmer, Wolfgang Wurst, Jan Rozman, Ruben Nogueiras, Meri De Angelis, Jeffery D. Molkentin, Natalie Krahmer, Chun-Xia Yi, Mathias V. Schmidt, Serge Luquet, Martin Heni, Matthias H. Tschöp, Paul T. Pfluger

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Figure 5

The Jnk-specific phosphatase Dusp8 ameliorates the inhibitory effect of Jnk signaling on glucocorticoid action.

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The Jnk-specific phosphatase Dusp8 ameliorates the inhibitory effect of ...
(A) Representative Western blot of an acute stimulation with the MAPK activator anisomycin (30 minutes) in HEK293 cells with Dusp8 overexpression (OE, confirmed by presence of Myc), compared with pCMV6 control vector. Densitometric analysis of anisomycin-induced phosphorylation of (B) Jnk, (C) c-Jun, (D) p38, and (E) ERK relative to β-actin (n = 3). (F) Representative Western blot and G) densitometric analysis of HEK293 cells with hGR OE and/or Dusp8 OE that were stimulated with and without anisomycin (30 minutes) and then analyzed for phosphorylated GR at Ser226 relative to total GR(n = 3). (H) GR luciferase reporter assay activity in HEK293 cells overexpressing Dusp8 or an empty control plasmid stimulated with dexamethasone (5 hours, n = 3 in biological triplicates). EtOH, ethanol. (I) Dexamethasone-induced GR luciferase reporter assay activity in HEK293 cells with Dusp8 OE that were pretreated with anisomycin (overnight, n = 3 in biological triplicates). (J) Western blot of hypothalami of HFD-fed (16 weeks) male Dusp8-KO and WT mice (n = 4 each). Genotypes were confirmed by PCR followed by agarose gel electrophoresis (WT = 370 bp, KO = 430 bp). (K–P) Densitometric analysis of phosphorylated Jnk, c-Jun, p38, and ERK as well as total protein levels of Jnk and c-Jun relative to GAPDH (n = 4 WT, n = 4 KO; 16 weeks HFD). (Q) Western blot and (R) densitometric analysis of phosphorylated GR at Ser226 relative to total GR in hypothalami of male Dusp8-KO (n = 4) and WT mice (n = 4). Data are shown as scatter dot plots. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by 1-way ANOVA (B–E and G) or Student’s t test (H, I, K–P, and R).

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