PMID- 25159329 OWN - NLM STAT- MEDLINE DCOM- 20150226 LR - 20211021 IS - 1522-1555 (Electronic) IS - 0193-1849 (Print) IS - 0193-1849 (Linking) VI - 307 IP - 9 DP - 2014 Nov 1 TI - Targeting steroid receptor coactivator 1 with antisense oligonucleotides increases insulin-stimulated skeletal muscle glucose uptake in chow-fed and high-fat-fed male rats. PG - E773-83 LID - 10.1152/ajpendo.00148.2014 [doi] AB - 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. FAU - Cantley, Jennifer L AU - Cantley JL AD - Howard Hughes Medical Institute and Departments of Internal Medicine and. FAU - Vatner, Daniel F AU - Vatner DF AD - Departments of Internal Medicine and. FAU - Galbo, Thomas AU - Galbo T AD - Departments of Internal Medicine and. FAU - Madiraju, Anila AU - Madiraju A AD - Departments of Internal Medicine and. FAU - Petersen, Max AU - Petersen M AD - Departments of Internal Medicine and. FAU - Perry, Rachel J AU - Perry RJ AD - Departments of Internal Medicine and. FAU - Kumashiro, Naoki AU - Kumashiro N AD - Howard Hughes Medical Institute and Departments of Internal Medicine and. FAU - Guebre-Egziabher, Fitsum AU - Guebre-Egziabher F AD - Departments of Internal Medicine and. FAU - Gattu, Arijeet K AU - Gattu AK AD - Departments of Internal Medicine and West Haven Veterans Affairs Medical Center, West Haven, Connecticut; FAU - Stacy, Mitchel R AU - Stacy MR AD - Departments of Internal Medicine and. FAU - Dione, Donald P AU - Dione DP AD - Departments of Internal Medicine and. FAU - Sinusas, Albert J AU - Sinusas AJ AD - Departments of Internal Medicine and. FAU - Ragolia, Louis AU - Ragolia L AD - Vascular Biology Institute, Winthrop-University Hospital, Mineola, New York. FAU - Hall, Christopher E AU - Hall CE AD - Vascular Biology Institute, Winthrop-University Hospital, Mineola, New York. FAU - Manchem, Vara Prasad AU - Manchem VP AD - Isis Pharmaceuticals, Carlsbad, California; and. FAU - Bhanot, Sanjay AU - Bhanot S AD - Isis Pharmaceuticals, Carlsbad, California; and. FAU - Bogan, Jonathan S AU - Bogan JS AD - Departments of Internal Medicine and Cell Biology, Yale School of Medicine, New Haven, Connecticut; FAU - Samuel, Varman T AU - Samuel VT AD - Departments of Internal Medicine and West Haven Veterans Affairs Medical Center, West Haven, Connecticut; Varman.Samuel@yale.edu. LA - eng GR - T32 DK101019/DK/NIDDK NIH HHS/United States GR - T32-HL-098069/HL/NHLBI NIH HHS/United States GR - R01 DK092661/DK/NIDDK NIH HHS/United States GR - P30-DK-45735/DK/NIDDK NIH HHS/United States GR - R24-DK-085638/DK/NIDDK NIH HHS/United States GR - UL1-RR-0241395/RR/NCRR NIH HHS/United States GR - T32 DK007058/DK/NIDDK NIH HHS/United States GR - P30 DK045735/DK/NIDDK NIH HHS/United States GR - R01-DK-092661/DK/NIDDK NIH HHS/United States GR - UL1 TR000142/TR/NCATS NIH HHS/United States GR - R01-DK-40936/DK/NIDDK NIH HHS/United States GR - R01-AG-23686/AG/NIA NIH HHS/United States GR - R01 DK075772/DK/NIDDK NIH HHS/United States GR - R01-DK-34989/DK/NIDDK NIH HHS/United States GR - R01-DK-088231/DK/NIDDK NIH HHS/United States GR - P30 DK034989/DK/NIDDK NIH HHS/United States GR - R01-DK-075772/DK/NIDDK NIH HHS/United States GR - P30-DK-034989/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20140826 PL - United States TA - Am J Physiol Endocrinol Metab JT - American journal of physiology. Endocrinology and metabolism JID - 100901226 RN - 0 (Enzyme Inhibitors) RN - 0 (Glucose Transporter Type 4) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Lipocalins) RN - 0 (Oligodeoxyribonucleotides, Antisense) RN - 0 (Slc2a4 protein, rat) RN - EC 2.3.1.48 (Nuclear Receptor Coactivator 1) RN - EC 4.1.1.32 (Pck1 protein, rat) RN - EC 4.1.1.32 (Phosphoenolpyruvate Carboxykinase (GTP)) RN - EC 5.3.- (Intramolecular Oxidoreductases) RN - EC 5.3.99.2 (prostaglandin R2 D-isomerase) RN - RXY07S6CZ2 (Prostaglandin D2) SB - IM MH - Adipose Tissue/drug effects/enzymology/metabolism MH - Animals MH - Biological Transport/drug effects MH - Diet, High-Fat/adverse effects MH - Enzyme Inhibitors/*therapeutic use MH - Gene Expression Regulation, Enzymologic/drug effects MH - Glucose Intolerance/*drug therapy/etiology/metabolism MH - Glucose Transporter Type 4/agonists/chemistry/metabolism MH - *Insulin Resistance MH - Intracellular Signaling Peptides and Proteins/agonists/genetics/metabolism MH - Intramolecular Oxidoreductases/genetics/metabolism MH - Lipocalins/agonists/genetics/metabolism MH - Liver/drug effects/enzymology/metabolism MH - Male MH - Muscle, Skeletal/*drug effects/metabolism MH - Nuclear Receptor Coactivator 1/*antagonists & inhibitors/genetics/metabolism MH - Oligodeoxyribonucleotides, Antisense/*therapeutic use MH - Phosphoenolpyruvate Carboxykinase (GTP)/genetics/metabolism MH - Prostaglandin D2/blood/metabolism MH - Protein Interaction Domains and Motifs MH - Proteolysis/drug effects MH - Rats, Sprague-Dawley PMC - PMC4216948 OTO - NOTNLM OT - glucose transporter type 4 OT - insulin resistance OT - skeletal muscle OT - white adipose tissue EDAT- 2014/08/28 06:00 MHDA- 2015/02/27 06:00 PMCR- 2015/11/01 CRDT- 2014/08/28 06:00 PHST- 2014/08/28 06:00 [entrez] PHST- 2014/08/28 06:00 [pubmed] PHST- 2015/02/27 06:00 [medline] PHST- 2015/11/01 00:00 [pmc-release] AID - ajpendo.00148.2014 [pii] AID - E-00148-2014 [pii] AID - 10.1152/ajpendo.00148.2014 [doi] PST - ppublish SO - Am J Physiol Endocrinol Metab. 2014 Nov 1;307(9):E773-83. doi: 10.1152/ajpendo.00148.2014. Epub 2014 Aug 26.