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Selective thyroid hormone receptor-beta activation: a strategy for reduction of weight, cholesterol, and lipoprotein
Gary J Grover1, Karin Mellström, Liu Ye
1Metabolic and Cardiovascular Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Pennington, NJ 08534, USA. groverg@bms.com
Abstract:
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).
Insights
Selective thyroid hormone receptor beta (TR beta) activation shows promise for treating obesity and high cholesterol. TR beta agonists, like KB-141, effectively reduce body weight and cholesterol without impacting heart rate in animal models and primates.
Area of Science:
- Endocrinology
- Pharmacology
- Metabolic Diseases
Background:
- Thyroid hormone receptors (TRs) regulate metabolism and cholesterol but have cardiac side effects.
- TR beta is implicated in cholesterol reduction and metabolic rate, while TR alpha influences heart rate.
- Existing obesity and hyperlipidemia treatments have limitations, necessitating novel therapeutic approaches.
Purpose of the Study:
- To investigate the effects of TR beta activation on metabolic rate and heart rate.
- To evaluate the therapeutic potential of selective TR beta agonists for obesity and hyperlipidemia.
Main Methods:
- Utilized TR alpha 1 knockout (TR alpha-/-) mice and wild-type (WT) mice to assess TR subtype-specific effects.
- Administered 3,5,3'-triiodi-l-thyronine (T3) and a selective TR beta agonist (KB-141) in mice, rats, and non-human primates.
- Measured metabolic rate (whole body oxygen consumption, MVO2), heart rate (HR), and cholesterol levels.
Main Results:
- T3 increased MVO2 in both WT and TR alpha-/- mice, suggesting roles for both TR alpha and TR beta.
- KB-141 demonstrated significant selectivity for increasing MVO2 over HR in mice and rats.
- KB-141 treatment led to reductions in cholesterol, lipoprotein (a), and body weight in primates, with no HR changes.
Conclusions:
- TR beta-selective agonists, such as KB-141, effectively reduce body weight, cholesterol, and lipoprotein (a).
- These agonists offer a potential therapeutic strategy for obesity and hypercholesterolemia with a favorable cardiac safety profile.
- TR beta-selective activation represents a promising new class of drugs for metabolic disorders.
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