kb-141 and Weight-Loss

Few treatments for obesity exist and improvements for treatment of hyperlipidemia are still desirable. Thyroid hormone receptors (TRs) regulate body weight, adiposity, and cholesterol levels. However, thyroid hormones can have deleterious effects, particularly cardiac acceleration, that limits the use of hormones in the treatment of obesity. There is evidence that the TRbeta subtype mediates lowering of blood cholesterol levels and possibly elevation of metabolic rate, whereas TRalpha appears to control heart rate. In studies, described in this review article, we examined the effects of selective TRbeta activation on metabolic rate and heart rate in mice, rats and monkeys. T3 had a greater effect on increasing heart rate in wild type (WT) than in TRalpha-/- mice (ED15 values of 34 and 469 nmol/kg/day, respectively). T3 increased metabolic rate (MVO2) in both WT and TRalpha-/- mice, but the effect on TRalpha-/- mice was less pronounced compared to WT mice. Stimulation of MVO2 is mediated by both TRalpha and TRbeta, but with different profiles. In cholesterol-fed rats, KB-141, a selective TRbeta agonist, increased MVO2 with a 10-fold selectivity and lowered cholesterol with a 27-fold selectivity vs. tachycardia. In primates, KB-141 caused significant, cholesterol, Lp(a) and body weight reduction after 1 week of treatment with no effect on heart rate. These data suggest that selective TRbeta agonists may represent a novel class of drugs for the treatment of obesity, hypercholesterolemia and elevated Lp(a), which may make them useful therapeutics for patients with metabolic syndrome.

Topics: Animals; Cholesterol; Heart; Heart Rate; Humans; Hypercholesterolemia; Obesity; Phenyl Ethers; Phenylacetates; Structure-Activity Relationship; Thyroid Hormone Receptors beta; Tissue Distribution; Weight Loss

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 alpha 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 TR alpha 1-/- 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 alpha-/- 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 alpha-/- mice, but the effect in the TR alpha 1-/- mice at the highest dose was half that of the WT mice. Thus, stimulation of MVO2 is likely due to both TR alpha and -beta. T3 had equivalent potency for cholesterol reduction in WT and TR alpha-/- mice. KB-141 increased MVO2 with selectivities of 16.5- and 11.2-fold vs. HR in WT and TR alpha 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. TR beta-selective agonists may constitute a previously uncharacterized class of drugs to treat obesity, hypercholesterolemia, and elevated lipoprotein (a).

Topics: Animals; Anticholesteremic Agents; Cardiovascular System; Cholesterol; Cholesterol, Dietary; Humans; In Vitro Techniques; Kinetics; Lipoprotein(a); Macaca fascicularis; Mice; Mice, Knockout; Phenyl Ethers; Phenylacetates; Rats; Rats, Sprague-Dawley; Receptors, Thyroid Hormone; Thyroid Hormone Receptors alpha; Thyroid Hormone Receptors beta; Triiodothyronine; Weight Loss