Sci. Aging Knowl. Environ., 6 August 2003
Souped-up thyroid hormone might make good as obesity treatment
Key Words: thyromimetic hypercholesterolemia cynomolgus monkeys agonist
Historically, thyroid hormone has been the lemon on the sketchy used car lot of antiobesity drugs. This chemical offers potential--but there's always been a catch. Now, scientists have shown that a new hormonelike molecule offers the body a good deal: increased metabolic rate without obvious side effects. The work suggests that drugs might one day coax the endocrine system to fight obesity.
Thyroid hormone reins in body weight and cholesterol concentrations, but it also stimulates irregular heartbeats. Scientists have linked some of these effects to the receptor proteins that transmit the hormone's signals through the cell. The receptor lowers cholesterol quantities, whereas the receptor regulates heart rate. About 5 years ago, researchers created a thyroid hormone analog that preferentially binds the receptor; this compound lowered quantities of lipids such as cholesterol without producing cardiac side effects in rodents. But the work left several uncertainties: Because the heart barely takes up the hormone analog--for unknown reasons--no one knew whether specificity alone rendered the drug safe. Furthermore, researchers had not yet assigned the weight-control function to a receptor; if the receptor raised metabolic rate, for example, perhaps they could manipulate it to trim body mass in addition to cutting cholesterol.
To find out whether the receptor by itself could speed metabolism, Gary Grover, a biologist at Bristol-Myers Squibb in Pennington, New Jersey, and colleagues administered normal thyroid hormone both to control mice and to those with a defective receptor gene. Because the body uses up oxygen as it squeezes energy out of food, they could assess metabolic rate by measuring the animals' oxygen consumption; it increased in both sets of rodents, indicating that stimulating the receptor can quicken metabolism on its own. Next, the researchers explored the potential of a new drug, dubbed KB-141, that binds the receptor almost exclusively but, unlike the previously studied compound, enters heart tissue. To assess whether KB-141 could fight obesity, the scientists fed it to mice, cholesterol-gobbling rats, and monkeys. It exerted a modest effect on the rodents--a 5% to 10% increase in the metabolic rates of the rats, for example. Testing metabolic rate in monkeys is extremely challenging, says Grover, but additional observations suggested that the drug might pare flab in the primates. After only a week of treatment, monkeys eating normal grub had lost 7% of their body weight. In all of the animals, KB-141 cut cholesterol concentrations but didn't alter heart rate.
The work highlights the potential of a relatively untapped fat-pruning strategy, says Gregory Brent, an endocrinologist at the University of California, Los Angeles. "The majority of pharmacological approaches to obesity have been for appetite and not increased metabolism," he says. With questions remaining about the safety and effectiveness of long-term -receptor stimulation, no one knows whether compounds such as KB-141 will eventually help dieters more than the traditional--and dangerous--thyroid hormones do. Modified thyroid hormones might one day offer a safe treatment for obesity, but in the meantime, shoppers trying to shed pounds should avoid the used car lot.
August 6, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150