PXD019451

PXD019451 is an original dataset announced via ProteomeXchange.

Title	Type 2 diabetes risk gene Dusp8 is a gatekeeper for hypothalamic Jnk signaling and insulin sensitivity
Description	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.
HostingRepository	PRIDE
AnnounceDate	2020-08-17
AnnouncementXML	Submission_2020-08-17_00:12:19.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Natalie Krahmer
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2020-05-28 05:08:59	ID requested
⏵ 1	2020-08-17 00:12:20	announced

Schriever SC, Kabra DG, Pfuhlmann K, Baumann P, Baumgart EV, Nagler J, Seebacher F, Harrison L, Irmler M, Kullmann S, Corr, ê, a-da-Silva F, Giesert F, Jain R, Schug H, Castel J, Martinez S, Wu M, H, ä, ring HU, de Angelis MH, Beckers J, M, ü, ller TD, Stemmer K, Wurst W, Rozman J, Nogueiras R, De Angelis M, Molkentin JD, Krahmer N, Yi CX, Schmidt MV, Luquet S, Heni M, Tsch, ö, p MH, Pfluger PT, Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity. J Clin Invest, 130(11):6093-6108(2020) [pubmed]

submitter keyword: Leptin, Dusp8, JNK, Type2 Diabetes

Natalie Krahmer
contact affiliation	Helmholtz-Diabetes Center
contact email	natalie.krahmer@helmholtz-muenchen.de
lab head
Natalie Krahmer
contact affiliation	Max Planck of Biochemistry
contact email	krahmer@biochem.mpg.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD019451
     1. Label: PRIDE project
     2. Name: Type 2 diabetes risk gene Dusp8 is a gatekeeper for hypothalamic Jnk signaling and insulin sensitivity