title: Transthyretin Antisense Oligonucleotides Lower Circulating RBP4 Levels and Improve Insulin Sensitivity in Obese Mice.
abstract: Circulating transthyretin (TTR) is a critical determinant of plasma retinol-binding protein 4 (RBP4) levels. Elevated RBP4 levels cause insulin resistance, and the lowering of RBP4 levels improves glucose homeostasis. Since lowering TTR levels increases renal clearance of RBP4, we determined whether decreasing TTR levels with antisense oligonucleotides (ASOs) improves glucose metabolism and insulin sensitivity in obesity. TTR-ASO treatment of mice with genetic or diet-induced obesity resulted in an 80-95% decrease in circulating levels of TTR and RBP4. Treatment with TTR-ASOs, but not control ASOs, decreased insulin levels by 30-60% and improved insulin sensitivity in ob/ob mice and high-fat diet-fed mice as early as after 2 weeks of treatment. The reduced insulin levels were sustained for up to 9 weeks of treatment and were associated with reduced adipose tissue inflammation. Body weight was not changed. TTR-ASO treatment decreased LDL cholesterol in high-fat diet-fed mice. The glucose infusion rate during a hyperinsulinemic-euglycemic clamp was increased by 50% in high-fat diet-fed mice treated with TTR-ASOs, demonstrating improved insulin sensitivity. This was also demonstrated by 20% greater inhibition of hepatic glucose production, a 45-60% increase of glucose uptake into skeletal and cardiac muscle, and a twofold increase in insulin signaling in muscle. These data show that decreasing circulating TTR levels or altering TTR-RBP4 binding could be a potential therapeutic approach for the treatment of type 2 diabetes.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Laura
authors.initials: L
authors.lastname: Zemany
authors.affiliation: Isis Pharmaceuticals, Carlsbad, CA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhanot
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Odile D
authors.initials: OD
authors.lastname: Peroni
authors.affiliation: Isis Pharmaceuticals, Carlsbad, CA.
authors.forename: Susan F
authors.initials: SF
authors.lastname: Murray
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Moraes-Vieira
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Angela
authors.initials: A
authors.lastname: Castoldi
authors.affiliation: Isis Pharmaceuticals, Carlsbad, CA.
authors.forename: Prasad
authors.initials: P
authors.lastname: Manchem
authors.affiliation: Isis Pharmaceuticals, Carlsbad, CA.
authors.forename: Shuling
authors.initials: S
authors.lastname: Guo
authors.affiliation: Isis Pharmaceuticals, Carlsbad, CA.
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA bkahn@bidmc.harvard.edu.
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Kahn
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose; D001835:Body Weight / Q000187:drug effects; D004041:Dietary Fats / Q000009:adverse effects; D004435:Eating / Q000187:drug effects; D005786:Gene Expression Regulation / Q000502:physiology*; D015309:Glucose Clamp Technique; D007249:Inflammation; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism*; D054839:Retinol-Binding Proteins, Plasma / Q000235:genetics / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D016376:Oligonucleotides, Antisense; D011228:Prealbumin; C502487:Rbp4 protein, mouse; D054839:Retinol-Binding Proteins, Plasma