title: Second-generation antisense oligonucleotides against β-catenin protect mice against diet-induced hepatic steatosis and hepatic and peripheral insulin resistance.
abstract: Although mutations in the Wnt/β-catenin signaling pathway are linked with the metabolic syndrome and type 2 diabetes in humans, the mechanism is unclear. High-fat-fed male C57BL/6 mice were treated for 4 wk with a 2'-O-methoxyethyl chimeric antisense oligonucleotide (ASO) to decrease hepatic and adipose expression of β-catenin. β-Catenin mRNA decreased by ≈80% in the liver and by 70% in white adipose tissue relative to control ASO-treated mice. β-Catenin ASO improved hepatic insulin sensitivity and increased insulin-stimulated whole body glucose metabolism, as assessed during hyperinsulinemic-euglycemic clamp in awake mice. β-Catenin ASO altered hepatic lipid composition in high-fat-fed mice. There were reductions in hepatic triglyceride (44%, P < 0.05) and diacylglycerol content (60%, P < 0.01) but a 30% increase in ceramide content (P < 0.001). The altered lipid content was attributed to decreased expression of sn-1,2 diacylglycerol acyltransferase and mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase and an increase in serine palmitoyl transferase. The decrease in cellular diacyglycerol was associated with a 33% decrease in PKCε activation (P < 0.05) and 64% increase in Akt2 phosphorylation (P < 0.05). In summary, Reducing β-catenin expression decreases expression of enzymes involved in hepatic fatty acid esterification, ameliorates hepatic steatosis and lipid-induced insulin resistance.
authors.affiliation: *Department of Internal Medicine, Department of Cellular and Molecular Physiology, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA; West Haven Veterans Affairs Medical Center, West Haven, Connecticut, USA; and ISIS Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Violeta B
authors.initials: VB
authors.lastname: Popov
authors.affiliation: *Department of Internal Medicine, Department of Cellular and Molecular Physiology, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA; West Haven Veterans Affairs Medical Center, West Haven, Connecticut, USA; and ISIS Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Francois R
authors.initials: FR
authors.lastname: Jornayvaz
authors.affiliation: *Department of Internal Medicine, Department of Cellular and Molecular Physiology, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA; West Haven Veterans Affairs Medical Center, West Haven, Connecticut, USA; and ISIS Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Emin O
authors.initials: EO
authors.lastname: Akgul
authors.affiliation: *Department of Internal Medicine, Department of Cellular and Molecular Physiology, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA; West Haven Veterans Affairs Medical Center, West Haven, Connecticut, USA; and ISIS Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Kanda
authors.affiliation: *Department of Internal Medicine, Department of Cellular and Molecular Physiology, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA; West Haven Veterans Affairs Medical Center, West Haven, Connecticut, USA; and ISIS Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jurczak
authors.affiliation: *Department of Internal Medicine, Department of Cellular and Molecular Physiology, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA; West Haven Veterans Affairs Medical Center, West Haven, Connecticut, USA; and ISIS Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Dongyan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: *Department of Internal Medicine, Department of Cellular and Molecular Physiology, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA; West Haven Veterans Affairs Medical Center, West Haven, Connecticut, USA; and ISIS Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Abulizi
authors.initials: A
authors.lastname: Abudukadier
authors.affiliation: *Department of Internal Medicine, Department of Cellular and Molecular Physiology, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA; West Haven Veterans Affairs Medical Center, West Haven, Connecticut, USA; and ISIS Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Sachin K
authors.initials: SK
authors.lastname: Majumdar
authors.affiliation: *Department of Internal Medicine, Department of Cellular and Molecular Physiology, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA; West Haven Veterans Affairs Medical Center, West Haven, Connecticut, USA; and ISIS Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Blas
authors.initials: B
authors.lastname: Guigni
authors.affiliation: *Department of Internal Medicine, Department of Cellular and Molecular Physiology, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA; West Haven Veterans Affairs Medical Center, West Haven, Connecticut, USA; and ISIS Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Kitt Falk
authors.initials: KF
authors.lastname: Petersen
authors.affiliation: *Department of Internal Medicine, Department of Cellular and Molecular Physiology, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA; West Haven Veterans Affairs Medical Center, West Haven, Connecticut, USA; and ISIS Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Vara Prasad
authors.initials: VP
authors.lastname: Manchem
authors.affiliation: *Department of Internal Medicine, Department of Cellular and Molecular Physiology, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA; West Haven Veterans Affairs Medical Center, West Haven, Connecticut, USA; and ISIS Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhanot
authors.affiliation: *Department of Internal Medicine, Department of Cellular and Molecular Physiology, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA; West Haven Veterans Affairs Medical Center, West Haven, Connecticut, USA; and ISIS Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.affiliation: *Department of Internal Medicine, Department of Cellular and Molecular Physiology, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA; West Haven Veterans Affairs Medical Center, West Haven, Connecticut, USA; and ISIS Pharmaceuticals, Carlsbad, California, USA varman.samuel@yale.edu.
authors.forename: Varman T
authors.initials: VT
authors.lastname: Samuel
mesh_terms: D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D004041:Dietary Fats / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008055:Lipids / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C011439:1,2-diacylglycerol; D004041:Dietary Fats; D004075:Diglycerides; D005227:Fatty Acids; D007328:Insulin; D008055:Lipids; D016376:Oligonucleotides, Antisense; D020011:Protective Agents; D014280:Triglycerides; D051176:beta Catenin; D005947:Glucose
keywords: Wnt pathway; lipid-induced insulin resistance; nonalcoholic fatty liver disease