Egr-1 decreases adipocyte insulin sensitivity by tilting PI3K/Akt and MAPK signal balance in mice
| Autor: | Ning Shen, Chang Liu, Chao-Jun Li, Mingliang Zhang, Xiang Gao, Bin Xue, Xiao Yu, Fei-Yan Pan, Chen Wang, Weiping Jia, Qian Gao |
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| Rok vydání: | 2011 |
| Předmět: |
MAPK/ERK pathway
medicine.medical_specialty General Immunology and Microbiology General Neuroscience Insulin medicine.medical_treatment Biology medicine.disease General Biochemistry Genetics and Molecular Biology body regions chemistry.chemical_compound Endocrinology Insulin resistance chemistry Downregulation and upregulation Adipocyte Internal medicine medicine Molecular Biology Hyperinsulinism Protein kinase B hormones hormone substitutes and hormone antagonists PI3K/AKT/mTOR pathway |
| Zdroj: | The EMBO Journal. 30:3754-3765 |
| ISSN: | 0261-4189 |
| DOI: | 10.1038/emboj.2011.277 |
| Popis: | It is well known that insulin can activate both PI3K/Akt pathway, which is responsible for glucose uptake, and MAPK pathway, which is crucial for insulin resistance formation. But, it is unclear exactly how the two pathways coordinate to regulate insulin sensitivity upon hyperinsulinism stress of type 2 diabetes mellitus (T2DM). Here, we show that an early response transcription factor Egr-1 could tilt the signalling balance by blocking PI3K/Akt signalling through PTEN and augmenting Erk/MAPK signalling through GGPPS, resulting in insulin resistance in adipocytes. Egr-1, PTEN and GGPPS are upregulated in the fat tissue of T2DM patients and db/db mice. Egr-1 overexpression in epididymal fat induced systematic insulin resistance in wild-type mice, and loss of Egr-1 function improved whole-body insulin sensitivity in diabetic mice, which is mediated by Egr-1 controlled PI3K/Akt and Erk/MAPK signalling balance. Therefore, we have revealed, for the first time, the mechanism by which Egr-1 induces insulin resistance under hyperinsulinism stress, which provides an ideal pharmacological target since inhibiting Egr-1 can simultaneously block MAPK and augment PI3K/Akt activation during insulin stimulation. |
| Databáze: | OpenAIRE |
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