Anti-obesity, anti-diabetic, and lipid lowering effects of the thyroid receptor beta subtype selective agonist KB-141.
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.
Bryzgalova
Galina
G
Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-171 76, Sweden.
Effendic
Suad
S
Khan
Akhtar
A
Rehnmark
Stefan
S
Barbounis
Peter
P
Boulet
Jamie
J
Dong
Gao
G
Singh
Rajni
R
Shapses
Sue
S
Malm
Johan
J
Webb
Paul
P
Baxter
John D
JD
Grover
Gary J
GJ
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*
D019440:Anti-Obesity Agents; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; C478108:KB 141; D010647:Phenyl Ethers; D010648:Phenylacetates; D037042:Thyroid Hormone Receptors beta