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

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

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Figure 3

Elevated glucocorticoid action and impaired hypothalamic insulin sensitivity and sympathetic responsiveness in HFD-fed Dusp8-KO males.

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Elevated glucocorticoid action and impaired hypothalamic insulin sensiti...
(A) Gene transcripts of hepatic enzymes involved in glucose metabolism (n = 7 WT, n = 8 Dusp8-KO) and (B) glucoregulatory enzymes in skeletal muscle (n = 8 WT, n = 8 Dusp8-KO) in 17-week HFD–fed, male Dusp8-KO mice relative to WT controls. (C) Representative Western blot and (D) densitometric analysis of phosphorylated Akt relative to GAPDH in hypothalami of HFD-fed (17 weeks) Dusp8-KO and WT males that were acutely injected with 3 IU insulin/kg BW or saline as control and sacrificed 8 minutes later (n = 3). (E) Gene transcripts related to HPA axis regulation measured in the hypothalamus (n = 8 WT, n = 8 Dusp8-KO) and pituitary (n = 8 WT, n = 8 Dusp8-KO) as well as enzymes involved in steroid synthesis measured in the adrenals (n = 8 WT, n = 7 Dusp8-KO) of 17-week HFD–fed mice. Tissue-specific glucocorticoid action in (F) liver, (G) muscle, and (H) hypothalamus (n = 8 WT, n = 8 Dusp8-KO) analyzed by qPCR. (I–K) Norepinephrine (NE) tissue content before and 3 hours after α-MPT injection and (L–N) NE turnover rates in the liver, soleus, and pancreas of male Dusp8-WT and -KO mice exposed to HFD for 16 weeks (n = 6 for liver and soleus, n = 4 for pancreas). Data are shown as box-and-whisker-plots (A, B, and E–H), as scatter dot plots (D and L–N), or as means ± SEM (I–K). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by Student’s t test (A, B, E–H, and L–N), 1-way ANOVA (D), or 2-way ANOVA (I–K).