标题：Selective thyroid hormone receptor-β activation: A strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：17
页码：10067-10072
DOI：10.1073/pnas.1633737100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Few treatments for obesity exist and, whereas efficacious therapeutics for hyperlipidemia are available, further improvements are desirable. Thyroid hormone receptors (TRs) regulate both body weight and cholesterol levels. However, thyroid hormones also have deleterious effects, particularly on the heart. The TR{beta} subtype is involved in cholesterol lowering and possibly elevating metabolic rate, whereas TR appears to be more important for control of heart rate (HR). In the current studies, we examined the effect of TR{beta} activation on metabolic rate and HR with either TR1-/- mice or the selective TR{beta} agonist KB-141 in mice, rats, and monkeys. 3,5,3'-triiodi-L-thyronine (T3) had a greater effect on increasing HR in WT than in TR-/- mice (ED15 values of 34 and 469 nmol/kg/day, respectively). T3 increased metabolic rate [whole body oxygen consumption (MVO2)] in both WT and TR-/- mice, but the effect in the TR1-/- mice at the highest dose was half that of the WT mice. Thus, stimulation of MVO2 is likely due to both TR and -{beta}. T3 had equivalent potency for cholesterol reduction in WT and TR-/- mice. KB-141 increased MVO2 with selectivities of 16.5- and 11.2-fold vs. HR in WT and TR1-/- mice, respectively. KB-141 also increased MVO2 with a 10-fold selectivity and lowered cholesterol with a 27-fold selectivity vs. HR in rats. In primates, KB-141 caused significant cholesterol, lipoprotein (a), and body-weight reduction (up to 7% after 1 wk) with no effect on HR. TR{beta}-selective agonists may constitute a previously uncharacterized class of drugs to treat obesity, hypercholesterolemia, and elevated lipoprotein (a).
