title: Short-term in vivo inhibition of insulin receptor substrate-1 expression leads to insulin resistance, hyperinsulinemia, and increased adiposity.
abstract: 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.
authors.affiliation: Department of Internal Medicine, State University of Campinas, Campinas, Sao Paolo, Brazil.
authors.forename: Eliana P
authors.initials: EP
authors.lastname: Araújo
authors.forename: Cláudio T
authors.initials: CT
authors.lastname: De Souza
authors.forename: Alessandra L
authors.initials: AL
authors.lastname: Gasparetti
authors.forename: Mirian
authors.initials: M
authors.lastname: Ueno
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Boschero
authors.forename: Mário J A
authors.initials: MJ
authors.lastname: Saad
authors.forename: Lício A
authors.initials: LA
authors.lastname: Velloso
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001835:Body Weight; D004822:Epididymis / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4; D015151:Immunoblotting; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013347:Subcellular Fractions; D013997:Time Factors; D014018:Tissue Distribution; D014443:Tyrosine / Q000378:metabolism
chemical_list: D051275:Glucose Transporter Type 4; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; C495694:Slc2a4 protein, rat; D014443:Tyrosine; D012694:Serine; D005947:Glucose