Selective thyroid hormone receptor-β activation:: A strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability

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 TRbeta subtype is involved in cholesterol lowering and possibly elevating metabolic rate, whereas TRalpha appears to be more important for control of heart rate (HR). In the current studies, we examined the effect of TRbeta activation on metabolic rate and HR with either TRalpha(1)(-/-) mice or the selective TRbeta agonist KB-141 in mice, rats, and monkeys. 3,5,3'-triiodi-L-thyronine (T-3) had a greater effect on increasing HR in WT than in TRalpha(-/-) mice (ED15 values of 34 and 469 nmol/kg/day, respectively). T-3 increased metabolic rate [whole body oxygen consumption (MVO2)] in both WT and TRalpha(-/-) mice, but the effect in the TRalpha(1)(-/-) mice at the highest dose was half that of the WT mice. Thus, stimulation of MVO2 is likely due to both TRa and -beta. T-3 had equivalent potency for cholesterol reduction in WT and TRalpha(-/-) mice. KB-141 increased MVO2 with selectivities of 16.5- and 11.2-fold vs. HR in WT and TRalpha(1)(-/-) 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. TRbeta-selective agonists may constitute a previously uncharacterized class of drugs to treat obesity, hypercholesterolemia, and elevated lipoprotein (a).