Recent genome-wide association studies (GWAS) identified DUSP8, a dual-specificity phosphatase targeting MAP kinases, as type 2 diabetes (T2D) risk gene. Here, we unravel Dusp8 as 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 CRH 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 (HPA) 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 fMRI 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 novel hypothalamic factor that plays a functional role in the etiology of T2D.
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, Rubén Nogueiras, Meri De Angelis, Jeffery D. Molkentin, Natalie Krahmer, Chun-Xia Yi, Mathias V. Schmidt, Serge Luquet, Martin Heni, Matthias H. Tschoep, Paul T. Pfluger