Irs1 Serine 307 Promotes Insulin Sensitivity in Mice

Children's Hospital Boston, Harvard Medical School, MA 02115, USA.
Cell metabolism (Impact Factor: 17.57). 01/2010; 11(1):84-92. DOI: 10.1016/j.cmet.2009.11.003
Source: PubMed


Phosphorylation of the insulin receptor substrates (Irs) on serine residues-typified by Ser307 of rodent Irs1-is thought to mediate insulin resistance. To determine whether Ser307 negatively regulates Irs1 in vivo, we generated knockin mice in which Ser307 (human Ser312) was replaced with alanine (A/A). Unexpectedly, A/A mice that were fed a high-fat diet developed more severe insulin resistance than control mice, accompanied by enhanced pancreatic compensation and impaired muscle insulin signaling. Chow-fed mice whose livers lacked Irs2 but retained a single knockin allele (A/lox::LKO2) were profoundly insulin resistant (versus +/lox::LKO2 mice), and their hepatocytes showed impaired insulin signaling ex vivo. Similarly, mutant A307 Irs1 adenovirus only partially restored the response to injected insulin in mice lacking hepatic Irs1 and Irs2. Thus, contrary to the results of cell-based experiments, Ser307 in mice is a positive regulatory site that moderates the severity of insulin resistance by maintaining proximal insulin signaling.

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    • "On the other hand, JNK activation in AgRP neurons fails to promote cellautonomous and systemic insulin resistance, despite the fact that JNK-dependent serine phosphorylation of IRS-1 has been proposed to cause insulin resistance, at least in vitro (Aguirre et al., 2002). However, mice with a mutation of IRS-1 serine 307 to alanine, which prevents this phosphorylation, are surprisingly more insulin resistant under high-fat diet conditions than their control littermates (Copps et al., 2010). These results indicate that JNK activation does not necessarily result in "
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    Cell Reports 11/2014; 9:1495-1506. DOI:10.1016/j.celrep.2014.10.045 · 8.36 Impact Factor
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    • "Alternatively, phosphorylation of serine 307 may be necessary, but insufficient to inhibit IRS-1 activation. Furthermore, a recent study indicates that phosphorylation of IRS-1 at serine 307 can promote insulin sensitivity, as mice containing an IRS-1 serine 307 to alanine mutation were more insulin resistant than control mice after high-fat feeding [33]. "
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    PLoS ONE 10/2013; 8(10):e77851. DOI:10.1371/journal.pone.0077851 · 3.23 Impact Factor
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    • "We find this SNP is located within the DRE cluster 20449 (chr2:227013575-227022415), which targets a 500 kb downstream gene that encodes IRS1 (insulin receptor substrate 1). Because IRS1 signaling is essential for glucose homeostasis in liver (59), and is related with the insulin sensitivity (60) and resistance (61), it is likely that this SNP may affect the function of DRE, which may impact the expression of IRS1 and contribute to type II diabetes. Given the increasing awareness of disease-associated noncoding SNPs, our predictions provide a valuable resource for explaining the causal roles of disease-associated SNPs in DRE region. "
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