Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P56851 (epididymal)
 11,273 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adipocytes contain three major substrate proteins of the insulin receptor, termed IRS-1, IRS-2, and IRS-3. We demonstrated that IRS-1 and IRS-2 are located mainly in the low density microsome (LDM) fraction and are tyrosine phosphorylated in response to insulin stimulation, leading to phosphatidylinositol (PI) 3-kinase activation. In contrast, IRS-3 is located mainly in the plasma membrane (PM) fraction and contributes to PI 3-kinase activation in the PM fraction. The different cellular localizations of IRS proteins may account for the mechanism of insulin resistance induced by a high fat diet, considering that PI 3-kinase activation in the LDM fraction is reportedly essential for the translocation of GLUT4 in adipocytes. High fat feeding in rats increased both protein and mRNA levels of IRS-3 but decreased those of IRS-1 and IRS-2 in epididymal adipocytes. As a result, selective impairment of insulin-induced PI 3-kinase activation was observed in the LDM fraction, whereas PI 3-kinase activation was conserved in the PM fraction. This is the first report showing that different IRS proteins function in different subcellular compartments, which may contribute to determining the insulin sensitivity in adipocytes.
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PMID:Different subcellular distribution and regulation of expression of insulin receptor substrate (IRS)-3 from those of IRS-1 and IRS-2. 979 80

Insulin receptor substrate-1 (IRS-1) has an important role as an early intermediary between the insulin and IGF receptors and downstream molecules that participate in insulin and IGF-I signal transduction. Here we employed an antisense oligonucleotide (IRS-1AS) to inhibit whole-body expression of IRS-1 in vivo and evaluate the consequences of short-term inhibition of IRS-1 in Wistar rats. Four days of treatment with IRS-1AS reduced the expression of IRS-1 by 80, 75, and 65% (P < 0.05) in liver, skeletal muscle, and adipose tissue, respectively. This was accompanied by a 40% (P < 0.05) reduction in the constant of glucose decay during an insulin tolerance test, a 78% (P < 0.05) reduction in glucose consumption during a hyperinsulinemic-euglycemic clamp, and a 90% (P < 0.05) increase in basal plasma insulin level. The metabolic effects produced by IRS-1AS were accompanied by a significant reduction in insulin-induced [Ser (473)] Akt phosphorylation in liver (85%, P < 0.05), skeletal muscle (40%, P < 0.05), and adipose tissue (85%, P < 0.05) and a significant reduction in insulin-induced tyrosine phosphorylation of ERK in liver (20%, P < 0.05) and skeletal muscle (30%, P < 0.05). However, insulin-induced tyrosine phosphorylation of ERK was significantly increased (60%, P < 0.05) in adipose tissue of IRS-1AS-treated rats. In rats treated with IRS-1AS for 8 d, a 100% increase (P < 0.05) in relative epididymal fat weight and a 120% (P < 0.05) increase in nuclear expression of peroxisome proliferator-activated receptor-gamma were observed. Thus, acute inhibition of IRS-1 expression in rats leads to insulin resistance accompanied by activation of a growth-related pathway exclusively in white adipose tissue.
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PMID:Short-term in vivo inhibition of insulin receptor substrate-1 expression leads to insulin resistance, hyperinsulinemia, and increased adiposity. 1555 May 10

Insulin receptor signal transduction depends on the precise intracellular localization of signalling molecules. This study examines the compartmentalization and the insulin-induced translocation and tyrosine phosphorylation of insulin receptor substrates (IRS-1 and IRS-3) in epididymal white adipose tissue from adult and insulin-resistant old rats. We found that insulin induces the translocation of IRS-1 from plasma membrane (PM) and light microsomes (LM) to cytosol, whereas IRS-3 translocates from PM to LM and cytosol upon insulin stimulation. Old rat adipocytes are characterized by higher relative levels of IRS proteins, under basal conditions, in those fractions where they are intended to translocate in response to insulin and exhibit a higher phosphotyrosine content of IRS-1 and -3 in basal conditions and a lower maximal phosphorylation in response to insulin. Furthermore, old rat adipocytes are also characterized by a reduced ability of insulin to stimulate both, Akt/PKB activity and translocation of GLUT4 to the PM. We conclude that the lower stimulation of downstream insulin signalling involved in glucose metabolism in old rat adipocytes may be explained, at least in part, by the altered subcellular distribution of IRS-1 and -3 proteins. In addition, our data suggest that the mechanism of turning on/off insulin receptor-mediated signal is impaired with aging.
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PMID:Altered subcellular distribution of IRS-1 and IRS-3 is associated with defective Akt activation and GLUT4 translocation in insulin-resistant old rat adipocytes. 1644 97