Dataset Information

Type 2 diabetes risk gene Dusp8 is a gatekeeper for hypothalamic Jnk signaling and insulin sensitivity

ABSTRACT: Recent genome-wide association studies (GWAS) identified Dusp8, a dual-specificity phosphatase targeting MAP kinases, as type 2 diabetes 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 male Dusp8 KO mice, respectively. This sex-specific and rheostatic 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. In summary, our findings suggest GWAS-identified gene Dusp8 as novel hypothalamic factor that plays a functional role in the etiology of type 2 diabetes.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Hypothalamus

SUBMITTER: Natalie Krahmer

LAB HEAD: Natalie Krahmer

PROVIDER: PXD019451 | Pride | 2020-08-17

REPOSITORIES: Pride

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			Action	DRS
	16052020_FaSe_FAIMS_120_5070_collab_Dusp8KO_Easyphos01.raw	Raw
	16052020_FaSe_FAIMS_120_5070_collab_Dusp8KO_Easyphos02.raw	Raw
	16052020_FaSe_FAIMS_120_5070_collab_Dusp8KO_Easyphos03.raw	Raw
	16052020_FaSe_FAIMS_120_5070_collab_Dusp8KO_Easyphos04.raw	Raw
	16052020_FaSe_FAIMS_120_5070_collab_Dusp8KO_Easyphos05.raw	Raw

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

Schriever Sonja C SC Kabra Dhiraj G DG Pfuhlmann Katrin K Baumann Peter P Baumgart Emily V EV Nagler Joachim J Seebacher Fabian F Harrison Luke L Irmler Martin M Kullmann Stephanie S Corrêa-da-Silva Felipe F Giesert Florian F Jain Ruchi R Schug Hannah H Castel Julien J Martinez Sarah S Wu Moya M Häring Hans-Ulrich HU de Angelis Martin Hrabe MH Beckers Johannes J Müller Timo D TD Stemmer Kerstin K Wurst Wolfgang W Rozman Jan J Nogueiras Ruben R De Angelis Meri M Molkentin Jeffery D JD Krahmer Natalie N Yi Chun-Xia CX Schmidt Mathias V MV Luquet Serge S Heni Martin M Tschöp Matthias H MH Pfluger Paul T PT

The Journal of clinical investigation 20201101 11

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 ...[more]

PMID: 32780722

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Project description:A robust system using disease relevant cells to systematically evaluate the role in diabetes for loci identified through genome wide association studies (GWAS) is urgently needed. Toward this goal, we created isogenic mutant human embryonic stem cell (hESC) lines in GWAS-identified candidate diabetes genes including CDKAL1, KCNQ1 and KCNJ11, and used directed differentiation to evaluate the function of derivative human beta-like cells. The mutations did not affect the generation of insulin+ cells, but impaired insulin secretion both in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1-/- insulin+ cells also displayed hypersensitivity to lipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-/--specific defects by inhibiting the AP1 (FOS/JUN) pathway. These studies establish a platform using isogenic hESCs to evaluate the function of GWAS-identified loci, and identify a drug candidate that rescues gene-specific defects, paving the way to precision therapy of metabolic diseases.A robust system using disease relevant cells to systematically evaluate the role in diabetes for loci identified through genome wide association studies (GWAS) is urgently needed. Toward this goal, we created isogenic mutant human embryonic stem cell (hESC) lines in GWAS-identified candidate diabetes genes including CDKAL1, KCNQ1 and KCNJ11, and used directed differentiation to evaluate the function of derivative human beta-like cells. The mutations did not affect the generation of insulin+ cells, but impaired insulin secretion both in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1-/- insulin+ cells also displayed hypersensitivity to lipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-/--specific defects by inhibiting the AP1 (FOS/JUN) pathway. These studies establish a platform using isogenic hESCs to evaluate the function of GWAS-identified loci, and identify a drug candidate that rescues gene-specific defects, paving the way to precision therapy of metabolic diseases.