Current
drug therapies for
obesity are ineffective, and existing treatments for
lipid disorders can be further improved.
Thyroid hormones affect both conditions, although currently available nonselective thyromimetics are not clinically useful for such treatment due to cardiac side effects. Recent studies suggest that
thyroid hormone receptor subtype beta (TRbeta) selective agonists have a profile in which
cholesterol can be reduced with minimal
tachycardia. The purpose of this study was to determine whether modest (5-10%) increases in metabolic rate could also be observed with minimal
tachycardia after TRbeta stimulation. For these studies, the TRbeta selective agonist,
GC-1, was used to assess selectivity for
lipid-lowering and metabolic rate changes relative to
tachycardia. Studies in
cholesterol-fed rats (7 d treatment) showed that
GC-1 reduced
cholesterol (ED(50) = 190 nmol/kg x d) approximately 30 times more potently than it induced
tachycardia (ED(15) = 5451 nmol/kg x d). T(3) showed no potency difference between
cholesterol lowering and
tachycardia.
GC-1 showed approximately 10-fold selectivity for increasing metabolic rate (ED(5) = 477 nmol/kg x d) relative to
tachycardia compared with T(3), which showed no selectivity. In cynomolgus monkeys treated for 7 d, significant
cholesterol-lowering and
lipoprotein (a) reduction was noted for both T(3) and
GC-1, whereas no
tachycardia was observed for
GC-1, unlike T(3). T(3) and
GC-1 caused a significant (approximately 4%) reduction in
body weight in these animals. Therefore, selective TRbeta activation may be a potentially usefully treatment for
obesity and reduction of
low density lipoprotein cholesterol and reduction of the atherogenic risk factor
lipoprotein (a).