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.
View: Text | PDF
Research Article Metabolism Article has an altmetric score of 87

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

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

×

Figure 6

Glucose intolerance in HFD-fed male Dusp8-KO mice is mediated by Jnk.

Options: View larger image (or click on image) Download as PowerPoint
Glucose intolerance in HFD-fed male Dusp8-KO mice is mediated by Jnk. Re...
Representative immunohistochemical detection of c-Jun phosphorylation in hypothalamic slices of male (A) WT (n = 14) and (B) Dusp8-KO (n = 9) littermates after 18 weeks of HFD feeding and (C) counting of positively stained nuclei. (D) Pathway enrichment and (E) heatmap for MAPK signaling genes including Dusp8 from microarray analyses of laser-capture-microdissected ARC of HFD-fed Dusp8-KO (n = 4) and WT (n = 3) mice. Relative gene expression values are shown across samples (z scales to mean expression per row). (F) Body weight and (G) body composition, (H) plasma leptin levels, and (I) markers of hypothalamic inflammation of male Dusp8-KO (n = 7), Jnk1-Dusp8–dKO (n = 9), and Jnk1-KO (n = 8) mice relative to WT controls (n = 6) were measured after 18 weeks of HFD exposure. (J–M) Glucose tolerance (GTT) and insulin tolerance tests (ITT) were carried out after 16 weeks or 17 weeks of HFD exposure, respectively (n = 6 WT, n = 7 Dusp8-KO, n = 8 Jnk1-KO, n = 9 dKO). (N) Plasma insulin levels were measured in WT (n = 6), Dusp8-KO (n = 7), Jnk1-Dusp8–dKO (n = 9), and Jnk1-KO mice (n = 8) after 18 weeks of HFD exposure to calculate the HOMA-IR (O). (P) Plasma corticosterone levels were measured in WT (n = 6), Dusp8-KO (n = 7), Jnk1-Dusp8–dKO (n = 9), and Jnk1-KO mice (n = 7) after 18 weeks of HFD. Data are shown as box-and-whisker plots (C, F–I, K, and M–P) or as means ± SEM (J and L). Scale bars: 200 μm. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by Student’s t test (C), 1-way ANOVA (F–I, K, and M–P), or 2-way ANOVA (J and L).