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Schriever, S.C. ; Kabra, D.G. ; Pfuhlmann, K. ; Baumann, P. ; Baumgart, E.V. ; Nagler, J. ; Seebacher, F. ; Harrison, L. ; Irmler, M. ; Kullmann, S. ; Corrêa-da-Silva, F.* ; Giesert, F.H.H. ; Jain, R.* ; Schug, H.* ; Castel, J.* ; Martinez, S.* ; Wu, M. ; Häring, H.-U. ; Hrabě de Angelis, M. ; Beckers, J. ; Müller, T.D. ; Stemmer, K. ; Wurst, W. ; Rozman, J. ; Nogueiras, R.* ; de Angelis, M. ; Molkentin, J.D.* ; Krahmer, N. ; Yi, C.-X.* ; Schmidt, M.V.* ; Luquet, S.* ; Heni, M. ; Tschöp, M.H. ; Pfluger, P.T.

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

J. Clin. Invest., accepted (2020)
Postprint DOI Order publishers version
Open Access Green

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.

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Publication type Article: Journal article
Document type Scientific Article
Keywords Diabetes; Metabolism; Obesity
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Publisher American Society of Clinical Investigation
Reviewing status