Anti-obesity, anti-diabetic, and lipid lowering effects of the thyroid receptor β subtype selective agonist KB-141
Anti-obesity, anti-diabetic, and lipid lowering effects of the thyroid receptor β subtype selective agonist KB-141
复制标题
DOI：
10.1016/j.jsbmb.2008.06.010
复制
发表时间：
2008-09-01
影响因子：
4.1
通讯作者：
Grover, Gary J.
中科院分区：
文献类型：
--
作者：
Bryzgalova, Galina;Effendic, Suad;Grover, Gary J.
选择性甲状腺激素受体亚型-β（TR β）激动剂作为高胆固醇血症和肥胖症的潜在治疗已经受到关注，但作为糖尿病的治疗受到较少关注，部分原因是这种病症在甲状腺激素过量状态下没有改善。TR β选择性激动剂KB-141在瘦大鼠中诱导代谢率增加5-10%和血浆胆固醇水平降低而不发生心动过速，这与主要的活性甲状腺激素T-3不同。在目前的研究中，我们确定KB-141是否促进肥胖动物的体重减轻，以及它是否具有抗糖尿病作用。在p.o.后检查体重、肥胖（DEXA）和脂质水平。将KB-141以0.00547-0.547 mg/kg/天的剂量给予肥胖Zucker大鼠21天，并以0.5 mg/kg/天的剂量给予ob/ob小鼠7天。在大鼠中，KB-141在0.167和0.0547 mg/kg/天剂量下分别使体重减轻6%和8%，无心动过速，在0.167 mg/kg/天剂量下肥胖减少（5-6%）。在ob/ob小鼠中，KB-141降低了血清胆固醇（35%）、三酰甘油（35%）以及血清和肝脏游离脂肪酸（18-20%），而没有心动过速。用KB-141（0.0547或0.328 mg/kg/天，持续2周）治疗ob/ob小鼠，以剂量依赖性方式改善葡萄糖耐量和胰岛素敏感性，对心率无影响。因此，KB-141具有抗肥胖、降脂和抗糖尿病作用，且不会出现心动过速，这表明选择性TR β激活可能是减轻代谢综合征特征的有用策略。(C)2008爱思唯尔有限公司保留所有权利。
Selective thyroid hormone receptor subtype-beta (TR beta) 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 TR beta 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, T-3. 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 falfa rats at 0.00547-0.547 mg/kg/day for 21 days, and in ob/ob mice at 0.5 mg/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 TR beta activation may be useful strategy to attenuate features of the metabolic syndrome. (C) 2008 Elsevier Ltd. All rights reserved.