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EMBO J. 2011 Aug 9;30(18):3754-65. doi: 10.1038/emboj.2011.277.

Egr-1 decreases adipocyte insulin sensitivity by tilting PI3K/Akt and MAPK signal balance in mice.

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1
MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Nanjing, China.

Abstract

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.

PMID:
21829168
PMCID:
PMC3173797
DOI:
10.1038/emboj.2011.277
[Indexed for MEDLINE]
Free PMC Article
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