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J Biol Chem, Vol. 273, Issue 45, 29686-29692, November 6, 1998
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From The Third Department of Internal Medicine, 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.
Institute for Adult Diseases,
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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