Overexpression of the LAR (leukocyte antigen-related) protein-tyrosine phosphatase in muscle causes insulin resistance

Zabolotny, Janice M.; Kim, Young–Bum; Peroni, Odile D.; Kim, Jason K.; Pani, Michael A.; Boss, Olivier; Klaman, Lori D.; Kamatkar, Shubhangi; Shulman, Gerald I.; Kahn, Barbara B.; Neel, Benjamin G.

doi:10.1073/pnas.071050398

Cited by 113 publications

(79 citation statements)

References 47 publications

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“…In this regard, it is of interest that the guanine nucleotide exchange factor Trio, which can activate the phagocyte Nox in the absence of GDP-to-GTP exchange on Rac (121), is a widely expressed multidomain protein that also forms a complex with leukocyte antigen-related PTP (LAR) (122). LAR is a receptor-type transmembrane PTP localized to focal adhesions that has been implicated in the regulation of insulin receptor dephosphorylation and insulin resistance (29,123,124). Trio has two functional guanine nucleotide exchange factor domains, one with specificity for Rac and the other for Rho, as well as a protein serine kinase domain.…”

Section: Potential Role Of G-proteins In Insulin-stimulated H 2 O 2 Amentioning

confidence: 99%

Redox Paradox

2005

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Propelled by the identification of a small family of NADPH oxidase (Nox) enzyme homologs that produce superoxide in response to cellular stimulation with various growth factors, renewed interest has been generated in characterizing the signaling effects of reactive oxygen species (ROS) in relation to insulin action. Two key observations made >30 years ago-that oxidants can facilitate or mimic insulin action and that H 2 O 2 is generated in response to insulin stimulation of its target cells-have led to the hypothesis that ROS may serve as second messengers in the insulin action cascade. Specific molecular targets of insulin-induced ROS include enzymes whose signaling activity is modified via oxidative biochemical reactions, leading to enhanced insulin signal transduction. These positive responses to cellular ROS may seem "paradoxical" because chronic exposure to relatively high levels of ROS have also been associated with functional ␤-cell impairment and the chronic complications of diabetes. The best-characterized molecular targets of ROS are the protein-tyrosine phosphatases (PTPs) because these important signaling enzymes require a reduced form of a critical cysteine residue for catalytic activity. PTPs normally serve as negative regulators of insulin action via the dephosphorylation of the insulin receptor and its tyrosinephosphorylated cellular substrates. However, ROS can rapidly oxidize the catalytic cysteine of target PTPs, effectively blocking their enzyme activity and reversing their inhibitory effect on insulin signaling. Among the cloned Nox homologs, we have recently provided evidence that Nox4 may mediate the insulin-stimulated generation of cellular ROS and is coupled to insulin action via the oxidative inhibition of PTP1B, a PTP known to be a major regulator of the insulin signaling cascade. Further characterization of the molecular components of this novel signaling cascade, including the mechanism of ROS generated by insulin and the identification of various oxidation-sensitive signaling targets in insulin-sensitive cells, may provide a novel means of facilitating insulin action in states of insulin resistance.

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Section: Potential Role Of G-proteins In Insulin-stimulated H 2 O 2 Amentioning

confidence: 99%

Redox Paradox

2005

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“…It cannot be excluded, however, that high-fat feeding reduced the phosphorylation of only a small subset of tyrosine residues, not detectable by immunoblotting, and that dietary cod protein normalized phosphorylation on these residues. This has been recently proposed to explain normal IR/IRS-1 tyrosine phosphorylation in the face of impaired IRS-1-associated PI 3-kinase activity in mice overexpressing the leukocyte-antigen related (LAR) tyrosine phosphatase in muscle (25). Similarly, glucosamine-infused rats displayed normal insulin-stimulated tyrosine phosphorylation of these proximal elements of insulin signaling, but impaired activation of PI 3-kinase (26).…”

Section: Discussionmentioning

confidence: 95%

Dietary Cod Protein Restores Insulin-Induced Activation of Phosphatidylinositol 3-Kinase/Akt and GLUT4 Translocation to the T-Tubules in Skeletal Muscle of High-Fat-Fed Obese Rats

et al. 2003

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Diet-induced obesity is known to cause peripheral insulin resistance in rodents. We have recently found that feeding cod protein to high-fat-fed rats prevents the development of insulin resistance in skeletal muscle. In the present study, we have further explored the cellular mechanisms behind this beneficial effect of cod protein on skeletal muscle insulin sensitivity. Rats were fed a standard chow diet or a high-fat diet in which the protein source was either casein, soy, or cod proteins for 4 weeks. Whole-body and muscle glucose disposal were reduced by ϳ50% in rats fed high-fat diets with casein or soy proteins, but these impairments were not observed in animals fed cod protein. Insulin-induced tyrosine phosphorylation of the insulin receptor and insulin receptor substrate (IRS) proteins were similar in muscle of chow-and high-fat-fed rats regardless of the dietary protein source. However, IRS-1-associated phosphatidylinositol (PI) 3-kinase activity was severely impaired (؊60%) in muscle of high-fatfed rats consuming casein or soy protein. In marked contrast, feeding rats with cod protein completely prevented the deleterious effect of fat feeding on insulinstimulated PI 3-kinase activity. The activation of the downstream kinase Akt/PKB by insulin, assessed by in vitro kinase assay and phosphorylation of GSK-3␤, were also impaired in muscle of high-fat-fed rats consuming casein or soy protein, but these defects were also fully prevented by dietary cod protein. However, no effect of cod protein was observed on atypical protein kinase C activity. Normalization of PI 3-kinase/Akt activation by insulin in rats fed high-fat diets with cod protein was associated with improved translocation of GLUT4 to the T-tubules but not to the plasma membrane. Taken together, these results show that dietary cod protein is a natural insulin-sensitizing agent that appears to prevent obesity-linked muscle insulin resistance by normalizing insulin activation of the PI 3-kinase/Akt pathway and by selectively improving GLUT4 translocation to the Ttubules. Diabetes 52:29 -37, 2003

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“…4, the protein tyrosine phosphatase LAR (leukocyte antigen related) has previously been reported to be implicated in insulin sensitivity, and has not previously been shown to be regulated by any PPAR agonists. Since increased activity of this phosphatase may contribute to the pathogenesis of insulin resistance (Zabolotny et al 2001), and the mRNA expression level of PTP-LAR was increased by the high-fat diet and downregulated by the compound dosing, the observed regulation of Figure 2 Northern blots of apolipoprotein C-III (ApoC3) and peroxisomal enoyl-CoA:hydrotase-3-hydroxyacyl-CoA bifunctional enzyme (Bifunctional enzyme) in livers of rats treated with increasing concentrations of fenofibrate and Wy-14643. Expected dose-dependent expression profiles were observed for ApoC3 and bifunctional enzyme, whereas no regulation was observed for the control, 36B4.…”

Section: Resultsmentioning

confidence: 99%

Identification of hepatic transcriptional changes in insulin-resistant rats treated with peroxisome proliferator activated receptor-alpha agonists

Frederiksen¹,

Wulf²,

Wassermann³

et al. 2003

Journal of Molecular Endocrinology

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Peroxisome proliferator activated receptor (PPAR)-α controls the expression of multiple genes involved in lipid metabolism, and activators of PPAR-α, such as fibrates, are commonly used drugs in the treatment of hypertriglyceridemia and other dyslipidemic states. Recent data have also suggested a role for PPAR-α in insulin resistance and glucose homeostasis. In the present study, we have assessed the transcriptional and physiological responses to PPAR-α activation in a diet-induced rat model of insulin resistance. The two PPAR-α activators, fenofibrate and Wy-14643, were dosed at different concentrations in high-fat fed Sprague-Dawley rats, and the transcriptional responses were examined in liver using cDNA microarrays. In these analyses, 98 genes were identified as being regulated by both compounds. From this pool of genes, 27 correlated to the observed effect on plasma insulin, including PPAR-α itself and the leukocyte antigen-related protein tyrosine phosphatase (PTP-LAR). PTP-LAR was downregulated by both compounds, and showed upregulation as a result of the high-fat feeding. This regulation was also observed at the protein level. Furthermore, downregulation of PTP-LAR by fenofibric acid was demonstrated in rat FaO hepatoma cells in vitro, indicating that the observed regulation of PTP-LAR by fenofibrate and Wy-14643 in vivo is mediated as a direct effect of the PPAR agonists on the hepatocytes. PTP-LAR is one of the first genes involved in insulin receptor signaling to be shown to be regulated by PPAR-α agonists. These data suggest that factors apart from skeletal muscle lipid supply may influence PPAR-α-mediated amelioration of insulin resistance.

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Overexpression of the LAR (leukocyte antigen-related) protein-tyrosine phosphatase in muscle causes insulin resistance

Cited by 113 publications

References 47 publications

Redox Paradox

Redox Paradox

Dietary Cod Protein Restores Insulin-Induced Activation of Phosphatidylinositol 3-Kinase/Akt and GLUT4 Translocation to the T-Tubules in Skeletal Muscle of High-Fat-Fed Obese Rats

Identification of hepatic transcriptional changes in insulin-resistant rats treated with peroxisome proliferator activated receptor-alpha agonists

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