Development of the thyroid hormone receptor β-subtype agonist KB-141: A strategy for body weight reduction and lipid lowering with minimal cardiac side effects

Abstract

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 TRβ subtype mediates lowering of blood cholesterol levels and possibly elevation of metabolic rate, whereas TRα appears to control heart rate. In studies, described in this review article, we examined the effects of selective TRβ activation on metabolic rate and heart rate in mice, rats and monkeys. T 3 had a greater effect on increasing heart rate in wild type (WT) than in TRα-/- mice (ED15 values of 34 and 469 nmol/kg/day, respectively). T3 increased metabolic rate (MVO2) in both WT and TRα-/- mice, but the effect on TRα-/- mice was less pronounced compared to WT mice. Stimulation of MVO2 is mediated by both TRα and TRβ, but with different profiles. In cholesterol-fed rats, KB-141, a selective TRβ 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 TRβ 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. © 2005 Neva Press.