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Submitted on June 22, 2004
Accepted on November 10, 2004
Departments of Internal Medicine and Physiology and Biophysics, State University of Campinas, Brazil
* To whom correspondence should be addressed. E-mail: lavelloso{at}fcm.unicamp.br.
Insulin receptor substrate-1 (IRS-1) has an important role as an early intermediary between the insulin (IR) and insulin-like growth factor (IGF-IR) 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 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, by a 78% (P < 0.05) reduction in glucose consumption during a hyperinsulinemic-euglycemic clamp, and by 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 by 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 eight days, a 100% increase (P < 0.05) in relative epididymal fat weight and a 120% (P < 0.05) increase in nuclear expression of PPAR
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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