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.

Full-text preview

Available from:
  • Source
    • "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 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Activation of c-Jun N-terminal kinase 1 (JNK1)- and inhibitor of nuclear factor kappa-B kinase 2 (IKK2)-dependent signaling plays a crucial role in the development of obesity-associated insulin and leptin resistance not only in peripheral tissues but also in the CNS. Here, we demonstrate that constitutive JNK activation in agouti-related peptide (AgRP)-expressing neurons of the hypothalamus is sufficient to induce weight gain and adiposity in mice as a consequence of hyperphagia. JNK activation increases spontaneous action potential firing of AgRP cells and causes both neuronal and systemic leptin resistance. Similarly, activation of IKK2 signaling in AgRP neurons also increases firing of these cells but fails to cause obesity and leptin resistance. In contrast to JNK activation, IKK2 activation blunts insulin signaling in AgRP neurons and impairs systemic glucose homeostasis. Collectively, these experiments reveal both overlapping and nonredundant effects of JNK- and IKK-dependent signaling in AgRP neurons, which cooperate in the manifestation of the metabolic syndrome.
    Full-text · Article · Nov 2014 · Cell Reports
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Obesity places major demands on the protein folding capacity of the endoplasmic reticulum (ER), resulting in ER stress, a condition that promotes hepatic insulin resistance and steatosis. Here we identify the transcription factor, Kruppel-like factor 15 (KLF15), as an essential mediator of ER stress-induced insulin resistance in the liver. Mice with a targeted deletion of KLF15 exhibit increased hepatic ER stress, inflammation, and JNK activation compared to WT mice; however, KLF15 (-/-) mice are protected against hepatic insulin resistance and fatty liver under high-fat feeding conditions and in response to pharmacological induction of ER stress. The mammalian target of rapamycin complex 1 (mTORC1), a key regulator of cellular energy homeostasis, has been shown to cooperate with ER stress signaling pathways to promote hepatic insulin resistance and lipid accumulation. We find that the uncoupling of ER stress and insulin resistance in KLF15 (-/-) liver is associated with the maintenance of a low energy state characterized by decreased mTORC1 activity, increased AMPK phosphorylation and PGC-1α expression and activation of autophagy, an intracellular degradation process that enhances hepatic insulin sensitivity. Furthermore, in primary hepatocytes, KLF15 deficiency markedly inhibits activation of mTORC1 by amino acids and insulin, suggesting a mechanism by which KLF15 controls mTORC1-mediated insulin resistance. This study establishes KLF15 as an important molecular link between ER stress and insulin action.
    Full-text · Article · Oct 2013 · PLoS ONE
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Defining the target genes of distal regulatory elements (DREs), such as enhancer, repressors and insulators, is a challenging task. The recently developed Hi-C technology is designed to capture chromosome conformation structure by high-throughput sequencing, and can be potentially used to determine the target genes of DREs. However, Hi-C data are noisy, making it difficult to directly use Hi-C data to identify DRE–target gene relationships. In this study, we show that DREs–gene pairs that are confirmed by Hi-C data are strongly phylogenetic correlated, and have thus developed a method that combines Hi-C read counts with phylogenetic correlation to predict long-range DRE–target gene relationships. Analysis of predicted DRE–target gene pairs shows that genes regulated by large number of DREs tend to have essential functions, and genes regulated by the same DREs tend to be functionally related and co-expressed. In addition, we show with a couple of examples that the predicted target genes of DREs can help explain the causal roles of disease-associated single-nucleotide polymorphisms located in the DREs. As such, these predictions will be of importance not only for our understanding of the function of DREs but also for elucidating the causal roles of disease-associated noncoding single-nucleotide polymorphisms.
    Full-text · Article · Sep 2013 · Nucleic Acids Research
Show more