Action of Insulin Receptor Substrate-3 (IRS-3) and IRS-4 to Stimulate Translocation of GLUT4 in Rat Adipose Cells

Zhou, Lixin; Chen, Hui; Xu, Pin; Cong, Li-Na; Sciacchitano, Salvatore; Li, Yunhua; Graham, David E.; Jacobs, Aviva R.; Taylor, Simeon I.; Quon, Michael J.

doi:10.1210/mend.13.3.0242

Cited by 51 publications

(37 citation statements)

References 45 publications

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“…This slight mRNA inhibition was also observed in the current study, especially in cells under insulin treatment, suggesting a direct relationship between VC and insulin resistance/sensitivity pathways. It has been described earlier that Irs3 overexpression induces higher translocation of GLUT4 proteins to the membranes of rat adipose cells, and also that mutant and non-functional IRS3 inhibits insulin action (Zhou et al 1999). Consequently, down-regulation of this gene could have contributed to the observed glucose uptake VC-mediated inhibition.…”

Section: Discussionmentioning

confidence: 91%

Vitamin C inhibits leptin secretion and some glucose/lipid metabolic pathways in primary rat adipocytes

García-Díaz

Campión²,

Milagro³

et al. 2010

Journal of Molecular Endocrinology

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Antioxidant-based treatments are emerging as an interesting approach to possibly counteract obesity fat accumulation complications, since this is accompanied by an increased systemic oxidative stress. The aim of this study was to analyze specific metabolic effects of vitamin C (VC) on epididymal primary rat adipocytes. Cells were isolated and incubated for 72 h in culture medium, in the absence or presence of 1 . 6 nM insulin, within a range of VC concentrations (5-1000 mM).Glucose-and lipid-related variables as well as the secretion/expression patterns of several obesity-related genes were assessed. It was observed that VC dose dependently inhibited glucose uptake and lactate production, and also reduced glycerol release in both control and insulin-treated cells. Also, VC caused a dramatic concentration-dependent fall in leptin secretion especially in insulin-stimulated cells. In addition, VC (200 mM) induced Cdkn1a and Casp8, partially inhibited Irs3, and together with insulin drastically reduced Gpdh (listed as Gpd1 in the MGI database) gene expressions. Finally, VC and insulin down-regulatory effects were observed on extracellular and intracellular reactive oxygen species production respectively. In summary, this experimental assay describes a specific effect of VC in isolated rat adipocytes on glucose and fat metabolism, and on the secretion/expression of important obesity-related proteins.

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Section: Discussionmentioning

confidence: 91%

Vitamin C inhibits leptin secretion and some glucose/lipid metabolic pathways in primary rat adipocytes

García-Díaz

Campión²,

Milagro³

et al. 2010

Journal of Molecular Endocrinology

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“…It is possible, however, that PI 3-kinase activation mediated via IRS-3 in the PM fraction contributes to the translocation of GLUT4. Indeed, increased translocation of GLUT4 has been demonstrated in rat adipose cells that overexpress IRS-3 (43). A more recent report, however, has shown that insulin-stimulated glucose transport in adipocytes from IRS-3-null mice is the same as in wild-type mice (44).…”

Section: Discussionmentioning

confidence: 97%

Subcellular Localization of Insulin Receptor Substrate Family Proteins Associated With Phosphatidylinositol 3-Kinase Activity and Alterations in Lipolysis in Primary Mouse Adipocytes From IRS-1 Null Mice

et al. 2001

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To clarify the roles of insulin receptor substrate (IRS) family proteins in phosphatidylinositol (PI) 3-kinase activation and insulin actions in adipocytes, we investigated the intracellular localization of IRS family proteins and PI 3-kinase activation in response to insulin by fractionation of mouse adipocytes from wild-type and IRS-1 null mice. In adipocytes from wild-type mice, tyrosine-phosphorylated IRS-1 and IRS-2, which were found to associate with PI 3-kinase in response to insulin, were detected in the plasma membrane (PM) and low-density microsome (LDM) fractions. By contrast, tyrosine-phosphorylated IRS-3 (pp60), which was found to associate with PI 3-kinase, was predominantly localized in the PM fraction. In adipocytes from IRS-1-null mice, insulin-stimulated PI 3-kinase activity in anti-phosphotyrosine (␣PY) immunoprecipitates in the LDM fraction was almost exclusively mediated via IRS-2 and was reduced to 25%; however, insulin-stimulated PI 3-kinase activity in the PM fraction was primarily mediated via IRS-3 and was reduced to 60%. To determine the potential functional impact of the distinct subcellular localization of IRSs and associating PI 3-kinase activity on adipocyte-specific metabolic actions, we examined lipolysis in IRS-1 null mice. The level of isoproterenol-induced lipolysis was increased 5.1-fold in adipocytes from IRS-1 null mice as compared with wildtype mice. Moreover, hormone-sensitive lipase (HSL) protein was increased 4.3-fold in adipocytes from IRS-1-null mice compared with wild-type mice, and HSL mRNA expression was also increased. The antilipolytic effect of insulin in IRS-1 null adipocytes, however, was comparable to that in wild-type mice. Thus, discordance between these two insulin actions as well as the transcriptional and translational effect (HSL mRNA and protein regulation) and the PM effect (antilipolysis) of insulin may be explained by distinct roles of both PI 3-kinase activity associated with IRS-1/IRS-2 and PI 3-kinase activity associated with IRS-3 in insulin actions related to their subcellular localization. Diabetes 50:1455-1463, 2001I nsulin stimulates the tyrosine phosphorylation (via the tyrosine kinase of the insulin receptor) of several endogenous substrates, such as insulin receptor substrate (IRS) family proteins, Grb2-associated binder-1, and Shc (1-11). These proteins interact through their phosphotyrosine residues with Src homology-2 (SH2) domain-containing proteins, such as the regulatory 85-kDa subunit (p85) of phosphatidylinositol (PI) 3-kinase, Grb2, Crk,. Among these, PI 3-kinase activity has been shown to be required for metabolic actions of insulin, such as glucose transport, glycogen synthesis, and antilipolysis (16 -18). The IRS family proteins IRS-1, -2, -3, and -4 contain a conserved pleckstrin homology (PH) domain and a phosphotyrosine-binding (PTB) domain that interacts with a phosphorylated NPXY motif in the insulin receptor at the NH 2 -terminus (3-9).IRS-1 has been shown to be the major substrate of the insulin receptor kinase, and we ...

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“…IRS-3 undergoes tyrosine phosphorylation in rodent adipocytes, leading to activation of phosphatidylinositol 3-kinase, among other possible downstream signalling pathways [4,13,14,19,20,21]. The human and mouse IRS-1 and IRS-2 proteins are 89% and 83% identical respectively [22].…”

Section: Discussionmentioning

confidence: 99%

Absence of functional insulin receptor substrate-3 ( IRS-3 ) gene in humans

Björnholm

Attersand

et al. 2002

Diabetologia

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Aim/hypothesis. Insulin receptor substrate (IRS) proteins play important roles in insulin action and pancreatic beta-cell function. At least four mammalian IRS molecules have been identified. Although genes and cDNAs encoding human IRS-1, IRS-2, and IRS-4 have been cloned, IRS-3 has been identified only in rodents. Thus, we have attempted to clone the human IRS-3 gene. Methods. Insulin-stimulated rat or human adipocytes were subjected to Western blot analysis to assess IRS-3 tyrosine phosphorylation. Human liver and adipose cDNA libraries were screened in an effort to clone IRS-3 cDNA. A PCR-based approach was designed to amplify IRS-3 cDNA. Reverse transcription PCR was carried out using mRNA from adipose tissue, liver, and skeletal muscle as templates in combination with an in silico screen using mouse IRS-1, IRS-2 and IRS-3 in a tblastn search of the draft public human genome.Results. In human adipocytes we did not detect a M r 60 000 phosphoprotein corresponding to IRS-3, whereas in rat adipocytes IRS-3 protein and insulinstimulated tyrosine phosphorylation was readily observed. None of the molecular approaches provided evidence for a functional IRS-3 gene in human tissue. Two deletions in human IRS-3 gene were identified using bioinformatics. The human IRS-3 gene product is predicted to lack a phosphotyrosine binding domain and also the sequence corresponding amino acid 353-407 of murine IRS-3. The contiguous sequence of genomic DNA between these two homologous regions does not have the coding information for human IRS-3. Conclusion/interpretation. In silico screening of the human IRS-3 genome region, combined with further biological and molecular validation, provides evidence against a functional IRS-3 in humans. [Diabetologia (2002[Diabetologia ( ) 45:1697[Diabetologia ( -1702

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Action of Insulin Receptor Substrate-3 (IRS-3) and IRS-4 to Stimulate Translocation of GLUT4 in Rat Adipose Cells

Cited by 51 publications

References 45 publications

Vitamin C inhibits leptin secretion and some glucose/lipid metabolic pathways in primary rat adipocytes

Vitamin C inhibits leptin secretion and some glucose/lipid metabolic pathways in primary rat adipocytes

Subcellular Localization of Insulin Receptor Substrate Family Proteins Associated With Phosphatidylinositol 3-Kinase Activity and Alterations in Lipolysis in Primary Mouse Adipocytes From IRS-1 Null Mice

Absence of functional insulin receptor substrate-3 ( IRS-3 ) gene in humans

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