1. Targeting steroid receptor coactivator 1 with antisense oligonucleotides increases insulin-stimulated skeletal muscle glucose uptake in chow-fed and high-fat-fed male rats.
- Author
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Cantley JL, Vatner DF, Galbo T, Madiraju A, Petersen M, Perry RJ, Kumashiro N, Guebre-Egziabher F, Gattu AK, Stacy MR, Dione DP, Sinusas AJ, Ragolia L, Hall CE, Manchem VP, Bhanot S, Bogan JS, and Samuel VT
- Subjects
- Adipose Tissue drug effects, Adipose Tissue enzymology, Adipose Tissue metabolism, Animals, Biological Transport drug effects, Diet, High-Fat adverse effects, Gene Expression Regulation, Enzymologic drug effects, Glucose Intolerance etiology, Glucose Intolerance metabolism, Glucose Transporter Type 4 agonists, Glucose Transporter Type 4 chemistry, Glucose Transporter Type 4 metabolism, Intracellular Signaling Peptides and Proteins agonists, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Intramolecular Oxidoreductases genetics, Intramolecular Oxidoreductases metabolism, Lipocalins agonists, Lipocalins genetics, Lipocalins metabolism, Liver drug effects, Liver enzymology, Liver metabolism, Male, Muscle, Skeletal metabolism, Nuclear Receptor Coactivator 1 genetics, Nuclear Receptor Coactivator 1 metabolism, Phosphoenolpyruvate Carboxykinase (GTP) genetics, Phosphoenolpyruvate Carboxykinase (GTP) metabolism, Prostaglandin D2 blood, Prostaglandin D2 metabolism, Protein Interaction Domains and Motifs, Proteolysis drug effects, Rats, Sprague-Dawley, Enzyme Inhibitors therapeutic use, Glucose Intolerance drug therapy, Insulin Resistance, Muscle, Skeletal drug effects, Nuclear Receptor Coactivator 1 antagonists & inhibitors, Oligodeoxyribonucleotides, Antisense therapeutic use
- Abstract
The steroid receptor coactivator 1 (SRC1) regulates key metabolic pathways, including glucose homeostasis. SRC1(-/-) mice have decreased hepatic expression of gluconeogenic enzymes and a reduction in the rate of endogenous glucose production (EGP). We sought to determine whether decreasing hepatic and adipose SRC1 expression in normal adult rats would alter glucose homeostasis and insulin action. Regular chow-fed and high-fat-fed male Sprage-Dawley rats were treated with an antisense oligonucleotide (ASO) against SRC1 or a control ASO for 4 wk, followed by metabolic assessments. SRC1 ASO did not alter basal EGP or expression of gluconeogenic enzymes. Instead, SRC1 ASO increased insulin-stimulated whole body glucose disposal by ~30%, which was attributable largely to an increase in insulin-stimulated muscle glucose uptake. This was associated with an approximately sevenfold increase in adipose expression of lipocalin-type prostaglandin D2 synthase, a previously reported regulator of insulin sensitivity, and an approximately 70% increase in plasma PGD2 concentration. Muscle insulin signaling, AMPK activation, and tissue perfusion were unchanged. Although GLUT4 content was unchanged, SRC1 ASO increased the cleavage of tether-containing UBX domain for GLUT4, a regulator of GLUT4 translocation. These studies point to a novel role of adipose SRC1 as a regulator of insulin-stimulated muscle glucose uptake.
- Published
- 2014
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