ArticleThe Journal of clinical investigation2020
Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity.
Article in The Journal of clinical investigation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 34 citations in OpenAlex.
- DUSP family phosphatases in cell signaling, inflammation, and chronic diseases.Journal of biomedical science · 2026Review
- Impact of miR-181a-5p and miR-1249-3p treatment on the visceral adipose tissue transcriptome of female mice.GeroScience · 2026Article
- Attack of the kinases: JNK signaling in metabolism.American journal of physiology. Regulatory, integrative and comparative physiology · 2026Review
- MAP kinase phosphatases in metabolic diseases.Trends in endocrinology and metabolism: TEM · 2026Review
- Is Hypothalamic Dysfunction a Cause of Type II Diabetes Mellitus?Neuroendocrinology · 2026Review
- Article
- Dual-specific phosphatases-8: a new target for clinical disease intervention.Journal of translational medicine · 2025Review
- Identifying disease progression biomarkers in metabolic associated steatotic liver disease (MASLD) through weighted gene co-expression network analysis and machine learning.Journal of translational medicine · 2025Article
- The JNK Signaling Pathway Regulates Seizures Through ENT1 in Pilocarpine-Induced Epilepsy Rat Model.CNS neuroscience & therapeutics · 2024Article
- The insulin resistant brain: impact on whole-body metabolism and body fat distribution.Diabetologia · 2024Review
- Targeting the Epigenetic Marks in Type 2 Diabetes Mellitus: Will Epigenetic Therapy Be a Valuable Adjunct to Pharmacotherapy?Diabetes, metabolic syndrome and obesity : targets and therapy · 2024Review
- DUSP8 induces TGF-β-stimulated IL-9 transcription and Th9-mediated allergic inflammation by promoting nuclear export of Pur-α.The Journal of clinical investigation · 2023Article
- Genome-Wide Association Study on the Content of Nucleotide-Related Compounds in Korean Native Chicken Breast Meat.Animals : an open access journal from MDPI · 2023Article
- Association of single-nucleotide polymorphisms in dual specificity phosphatase 8 and insulin-like growth factor 2 genes with inosine-5'-monophosphate, inosine, and hypoxanthine contents in chickens.Animal bioscience · 2023Article
- A Pathophysiological Intersection of Diabetes and Alzheimer's Disease.International journal of molecular sciences · 2022Review
- Genetic variation in satiety signaling and hypothalamic inflammation: merging fields for the study of obesity.The Journal of nutritional biochemistry · 2022Review
- MEHP induces pyroptosis and autophagy alternation by cathepsin B activation in INS-1 cells.Environmental science and pollution research international · 2021Article
- Dual-specificity phosphatase 8: A gatekeeper in hypothalamic control of glucose metabolism in males.Journal of diabetes investigation · 2021Article
- Nutrient infusion in the dorsal vagal complex controls hepatic lipid and glucose metabolism in rats.iScience · 2021Article
- Peripheral and central regulation of insulin by the intestine and microbiome.American journal of physiology. Endocrinology and metabolism · 2021Article
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Authors and funding
34 authors at 9 institutions in 10 countries.
Funding
No grant is acknowledged in the PubMed record.
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 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.
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