title: Targeting steroid receptor coactivator 1 with antisense oligonucleotides increases insulin-stimulated skeletal muscle glucose uptake in chow-fed and high-fat-fed male rats.
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.
authors.affiliation: Howard Hughes Medical Institute and Departments of Internal Medicine and.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Cantley
authors.affiliation: Departments of Internal Medicine and.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Vatner
authors.affiliation: Departments of Internal Medicine and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Galbo
authors.affiliation: Departments of Internal Medicine and.
authors.forename: Anila
authors.initials: A
authors.lastname: Madiraju
authors.affiliation: Departments of Internal Medicine and.
authors.forename: Max
authors.initials: M
authors.lastname: Petersen
authors.affiliation: Departments of Internal Medicine and.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Perry
authors.affiliation: Howard Hughes Medical Institute and Departments of Internal Medicine and.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kumashiro
authors.affiliation: Departments of Internal Medicine and.
authors.forename: Fitsum
authors.initials: F
authors.lastname: Guebre-Egziabher
authors.affiliation: Departments of Internal Medicine and West Haven Veterans Affairs Medical Center, West Haven, Connecticut;
authors.forename: Arijeet K
authors.initials: AK
authors.lastname: Gattu
authors.affiliation: Departments of Internal Medicine and.
authors.forename: Mitchel R
authors.initials: MR
authors.lastname: Stacy
authors.affiliation: Departments of Internal Medicine and.
authors.forename: Donald P
authors.initials: DP
authors.lastname: Dione
authors.affiliation: Departments of Internal Medicine and.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Sinusas
authors.affiliation: Vascular Biology Institute, Winthrop-University Hospital, Mineola, New York.
authors.forename: Louis
authors.initials: L
authors.lastname: Ragolia
authors.affiliation: Vascular Biology Institute, Winthrop-University Hospital, Mineola, New York.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Hall
authors.affiliation: Isis Pharmaceuticals, Carlsbad, California; and.
authors.forename: Vara Prasad
authors.initials: VP
authors.lastname: Manchem
authors.affiliation: Isis Pharmaceuticals, Carlsbad, California; and.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhanot
authors.affiliation: Departments of Internal Medicine and Cell Biology, Yale School of Medicine, New Haven, Connecticut;
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Bogan
authors.affiliation: Departments of Internal Medicine and West Haven Veterans Affairs Medical Center, West Haven, Connecticut; Varman.Samuel@yale.edu.
authors.forename: Varman T
authors.initials: VT
authors.lastname: Samuel
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D018149:Glucose Intolerance / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D054834:Lipocalins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D056920:Nuclear Receptor Coactivator 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense / Q000627:therapeutic use*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics / Q000378:metabolism; D015230:Prostaglandin D2 / Q000097:blood / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis / Q000187:drug effects; D017207:Rats, Sprague-Dawley
chemical_list: D004791:Enzyme Inhibitors; D051275:Glucose Transporter Type 4; D047908:Intracellular Signaling Peptides and Proteins; D054834:Lipocalins; D020319:Oligodeoxyribonucleotides, Antisense; C495694:Slc2a4 protein, rat; D056920:Nuclear Receptor Coactivator 1; C582554:Pck1 protein, rat; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D015230:Prostaglandin D2
keywords: glucose transporter type 4; insulin resistance; skeletal muscle; white adipose tissue