title: Anti-obesity, anti-diabetic, and lipid lowering effects of the thyroid receptor beta subtype selective agonist KB-141.
abstract: Selective thyroid hormone receptor subtype-beta (TRbeta) agonists have received attention as potential treatments for hypercholesterolemia and obesity, but have received less attention as treatments for diabetes, partly because this condition is not improved in thyroid hormone excess states. The TRbeta selective agonist KB-141 induces 5-10% increases in metabolic rate and lowering of plasma cholesterol levels without tachycardia in lean rats, unlike the major active thyroid hormone, T3. In the current study, we determined whether KB-141 promotes weight loss in obese animals and whether it exhibits anti-diabetogenic effects. Body weight, adiposity (DEXA), and lipid levels were examined following p.o. administration of KB-141 to obese Zucker fa/fa rats at 0.00547-0.547 mg/kg/day for 21 days, and in ob/ob mice at 0.5mg/kg/day KB-141 for 7 days. In rats, KB-141 reduced body weight by 6 and 8%, respectively, at 0.167 and 0.0547 mg/kg/day without tachycardia and adiposity was reduced at 0.167 mg/kg/day (5-6%). In ob/ob mice, KB-141 lowered serum cholesterol (35%), triacylglycerols (35%) and both serum and hepatic free fatty acids (18-20%) without tachycardia. Treatment of ob/ob mice with KB-141 (0.0547 or 0.328 mg/kg/day over 2 weeks) improved glucose tolerance and insulin sensitivity in a dose-dependent manner with no effect on heart rate. Thus, KB-141 elicits anti-obesity, lipid lowering and anti-diabetic effects without tachycardia suggesting that selective TRbeta activation may be useful strategy to attenuate features of the metabolic syndrome.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-171 76, Sweden.
authors.forename: Galina
authors.initials: G
authors.lastname: Bryzgalova
authors.forename: Suad
authors.initials: S
authors.lastname: Effendic
authors.forename: Akhtar
authors.initials: A
authors.lastname: Khan
authors.forename: Stefan
authors.initials: S
authors.lastname: Rehnmark
authors.forename: Peter
authors.initials: P
authors.lastname: Barbounis
authors.forename: Jamie
authors.initials: J
authors.lastname: Boulet
authors.forename: Gao
authors.initials: G
authors.lastname: Dong
authors.forename: Rajni
authors.initials: R
authors.lastname: Singh
authors.forename: Sue
authors.initials: S
authors.lastname: Shapses
authors.forename: Johan
authors.initials: J
authors.lastname: Malm
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.forename: John D
authors.initials: JD
authors.lastname: Baxter
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Grover
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D003920:Diabetes Mellitus / Q000188:drug therapy*; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008820:Mice, Obese; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy*; D010647:Phenyl Ethers / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010648:Phenylacetates / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011924:Rats, Zucker; D037042:Thyroid Hormone Receptors beta / Q000819:agonists*
chemical_list: D019440:Anti-Obesity Agents; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; C478108:KB 141; D010647:Phenyl Ethers; D010648:Phenylacetates; D037042:Thyroid Hormone Receptors beta