Positive and negative regulation of insulin signaling through IRS-1 phosphorylation

Gual, Philippe; Marchand-Brustel, Y. Le; Tanti, Jean‐François

doi:10.1016/j.biochi.2004.10.019

Cited by 764 publications

(630 citation statements)

References 108 publications

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“…Thus, the decrease in the observed level of IRS-1 Y612 phosphorylation may be the result of a reduced level of protein production rather than a change in the stoichiometry of phosphorylation. Based upon previous work documenting the inhibitory effect of phosphorylation of this residue on insulin signalling [34], we speculated that this may represent another way in which resistin leads to insulin resistance or degradation of IRS-1 [34]. However, we observed no change in the basal or insulin-stimulated total levels of IRS-1 phosphorylation on S616 after 24 h of resistin treatment.…”

Section: Discussionsupporting

confidence: 47%

Regulation of insulin signalling, glucose uptake and metabolism in rat skeletal muscle cells upon prolonged exposure to resistin

et al. 2005

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Aims/hypothesis: Debate exists regarding the role of resistin in the pathophysiology of insulin resistance. The aim of this study was to directly assess the effects of resistin (0-24 h) on basal and insulin-stimulated glucose uptake and metabolism in skeletal muscle cells and to investigate the mechanisms responsible for the effects of resistin. Methods: We used L6 rat skeletal muscle cells and examined [ 3 H]2-deoxyglucose uptake, GLUT4 translocation and GLUT protein content. We assessed glucose metabolism by measuring the incorporation of D-[U-14 C] glucose into glycogen, 14 CO 2 and lactate production, as well as the phosphorylation level and total protein content of insulin signalling proteins, including insulin receptor β-subunit (IRβ), insulin receptor substrate (IRS), Akt and glycogen synthase kinase-3β (GSK-3β). Results: Treatment of L6 rat skeletal muscle cells with recombinant resistin (50 nmol/l, 0-24 h) reduced levels of basal and insulin-stimulated 2-deoxyglucose uptake and decreased insulin-stimulated GLUT4myc content at the cell surface, with no alteration in the production of GLUT4 or GLUT1. Resistin also decreased glycogen synthesis and GSK-3β phosphorylation. Insulin-stimulated oxidation of glucose via the Krebs cycle was reduced by resistin, whereas lactate production was unaltered. Although insulin receptor protein level and phosphorylation were unaltered by resistin, production of IRS-1, but not IRS-2, was downregulated and a decreased tyrosine phosphorylation of IRS-1 was detected. Reduced phosphorylation of Akt on T308 and S473 was observed, while total Akt and Akt1, but not Akt2 or Akt3, production was decreased. Conclusions/ interpretation: Our data show that resistin regulates the function of IRS-1 and Akt1 and decreases GLUT4 translocation and glucose uptake in response to insulin. Selective decreases in insulin-stimulated glucose metabolism via oxidation and conversion to glycogen were also induced by resistin. These observations highlight the potential role of resistin in the pathophysiology of type 2 diabetes in obesity.

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Section: Discussionsupporting

confidence: 47%

Regulation of insulin signalling, glucose uptake and metabolism in rat skeletal muscle cells upon prolonged exposure to resistin

et al. 2005

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“…TNF is known to reduce adipose tissue mass by decreasing PPARG production, stimulating lipolysis and repressing genes involved in the uptake and metabolism of lipids and glucose [37][38][39][40][41]. Considering all this, the higher insulin sensitivity that we observed in our study in WAT and that was associated with higher expression of genes mediating insulin sensitivity (Irs1, Slc2a4, adiponectin) and lipogenesis (Srebf1, Fasn, Pparg) may be secondary to the tissue TNF and IL1B depletion, and might contribute to the increase in adipocyte volume seen in C3H/HeJ mice despite lower food intake.…”

Section: Discussionmentioning

confidence: 99%

C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet

et al. 2007

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Aims/hypothesis Inflammation is associated with obesity and has been implicated in the development of diabetes and atherosclerosis. During gram-negative bacterial infection, lipopolysaccharide causes an inflammatory reaction via toll-like receptor 4 (TLR4), which has an essential function in the induction of innate and adaptative immunity. Our aim was to determine what role TLR4 plays in the development of metabolic phenotypes during high-fat feeding. Materials and methods We evaluated metabolic consequences of a high-fat diet in TLR4 mutant mice (C3H/HeJ) and their respective controls. Results TLR4 inactivation reduced food intake without significant modification of body weight, but with higher epididymal adipose tissue mass and adipocyte hypertrophy. It also attenuated the inflammatory response and increased glucose transport and the expression levels of adiponectin and lipogenic markers in white adipose tissue. In addition, TLR4 inactivation blunted insulin resistance induced by lipopolysaccharide in differentiated adipocytes. Increased feeding efficiency in TLR4 mutant mice was associated with lower mass and lower expression of uncoupling protein 1 gene in brown adipose tissue. Finally, TLR4 inactivation slowed the development of hepatic steatosis, reducing the liver triacylglycerol content and also expression levels of lipogenic and fibrosis markers. Conclusions/interpretation TLR4 influences white adipose tissue inflammation and insulin sensitivity, as well as liver fat storage, and is important in the regulation of metabolic phenotype during a fat-enriched diet.

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“…It is generally accepted that the role of insulin may be related to signaling pathways activated by the binding of insulin to its receptor (IR) and the subsequent tyrosine phosphorylation of insulin receptor substrate (IRS) [28], [29], [30]. Insulin actions are generally transmitted through two distinct pathways: 1) phosphorylation of IRS with activation of phosphatidylinositol (PI) 3-kinase that mediates metabolic actions of insulin, and 2) the Ras/ MAPK pathway that mediates non-metabolic mitogenic and growth effects of insulin [28], [29], [30,31], [32].…”

Section: Discussionmentioning

confidence: 99%

Role of resistin in cardiac contractility and hypertrophy

Kim

Satoh

et al. 2008

Journal of Molecular and Cellular Cardiology

141

120

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Cardiovascular sequelae including diabetic cardiomyopathy constitute the major cause of death in diabetic patients. Although several factors may contribute to the development of this cardiomyopathy, the underlying molecular/cellular mechanisms leading to cardiac dysfunction are still partially understood. Recently, a novel paradigm for the role of the adipocytokine resistin in diabetes has emerged. Resistin has been proposed to be a link between obesity, insulin resistance and diabetes. Using microarray analysis, we have recently found that cardiomyocytes isolated from type 2 diabetic hearts express high levels of resistin. However, the function of resistin with respect to cardiac function is unknown. In this study we show that resistin is not only expressed in the heart, but also promotes cardiac hypertrophy. Adenovirus-mediated overexpression of resistin in cultured neonatal rat ventricular myocytes (NRVM) significantly increased sarcomere organization and cell size, increased protein synthesis and increased the expression of atrial natriuretic factor and β-myosin heavy chain. Overexpression of resistin in NRVM was also associated with activation of the mitogenactivated protein (MAP) kinases, ERK1/2 and p38, as well as increased Ser-636 phosphorylation of insulin receptor substrate-1 (IRS-1), indicating that IRS-1/MAPK pathway may be involved in the observed hypertrophic response. Overexpression of resistin in adult cultured cardiomyocytes significantly altered myocyte mechanics by depressing cell contractility as well as contraction and relaxation velocities. Intracellular Ca 2+ measurements showed slower Ca 2+ transients decay in resistin-transduced myocytes compared to controls, suggesting impaired cytoplasmic Ca 2+ clearing or alterations in myofilament activation. We conclude that resistin overexpression alters cardiac contractility, confers to primary cardiomyocytes all the features of the hypertrophic phenotype and promotes cardiac hypertrophy possibly via the IRS-1/MAPK pathway.

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Positive and negative regulation of insulin signaling through IRS-1 phosphorylation

Cited by 764 publications

References 108 publications

Regulation of insulin signalling, glucose uptake and metabolism in rat skeletal muscle cells upon prolonged exposure to resistin

Regulation of insulin signalling, glucose uptake and metabolism in rat skeletal muscle cells upon prolonged exposure to resistin

C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet

Role of resistin in cardiac contractility and hypertrophy

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