Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity
(2020) In Journal of Clinical Investigation 130(11). p.6093-6108- 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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2020
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Clinical Investigation
- volume
- 130
- issue
- 11
- pages
- 16 pages
- publisher
- The American Society for Clinical Investigation
- external identifiers
-
- scopus:85094654200
- pmid:32780722
- ISSN
- 0021-9738
- DOI
- 10.1172/JCI136363
- language
- English
- LU publication?
- yes
- id
- 100e1df4-58ed-4489-833d-b935d9b29152
- date added to LUP
- 2020-11-13 12:09:23
- date last changed
- 2024-06-12 23:52:09
@article{100e1df4-58ed-4489-833d-b935d9b29152,
abstract = {{<p>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.</p>}},
author = {{Schriever, Sonja C. and Kabra, Dhiraj G. and Pfuhlmann, Katrin and Baumann, Peter and Baumgart, Emily V. and Nagler, Joachim and Seebacher, Fabian and Harrison, Luke and Irmler, Martin and Kullmann, Stephanie and Corrêa-Da-Silva, Felipe and Giesert, Florian and Jain, Ruchi and Schug, Hannah and Castel, Julien and Martinez, Sarah and Wu, Moya and Häring, Hans Ulrich and de Angelis, Martin Hrabe and Beckers, Johannes and Müller, Timo D. and Stemmer, Kerstin and Wurst, Wolfgang and Rozman, Jan and Nogueiras, Ruben and de Angelis, Meri and Molkentin, Jeffery D. and Krahmer, Natalie and Yi, Chun Xia and Schmidt, Mathias V. and Luquet, Serge and Heni, Martin and Tschöp, Matthias H. and Pfluger, Paul T.}},
issn = {{0021-9738}},
language = {{eng}},
number = {{11}},
pages = {{6093--6108}},
publisher = {{The American Society for Clinical Investigation}},
series = {{Journal of Clinical Investigation}},
title = {{Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity}},
url = {{http://dx.doi.org/10.1172/JCI136363}},
doi = {{10.1172/JCI136363}},
volume = {{130}},
year = {{2020}},
}