It is well known that thyroid hormone levels have an impact on the rate of metabolism and body weight. Low levels of thyroid hormone are associated with weight gain and increased levels of cholesterol and lipoproteins. High levels of thyroid hormone are associated with weight loss and low levels of cholesterol and lipoproteins.

Increasing thyroid hormone levels would therefore seem like an easy method for increasing the metabolism and losing weight. Unfortunately life is not as simple as this. The stimulation of the metabolism also extends to stimulation of the heart. Thyroid hormone causes the heart to beat faster and more strongly. As a result, people with excess levels of thyroid hormone normally experience a racing heart beat (tachycardia) and palpitations. Sustained stimulation of the heart in this way can cause lasting damage.

Thyroid hormone is consequently not recommended for weight loss.

Research just published by the National Academy of Science¹ is therefore very interesting. Gary Grover and a group of other researchers associated with Bristol-Myers Squibb set out to determine whether it was possible to stimulate the metabolism and thereby reduce body weight, cholesterol and lipoproteins without stimulating the heart. Their approach was to exploit one of the subtle elements of thyroid hormone action.

Thyroid hormone does its work by binding to Thyroid Receptors (TRs) in the nucleus of the cells. There are two types of thyroid receptors, TRa and TRb.³ These receptors are each expressed in different quantities in different cells. Mice that have had the gene that produces TRa disrupted have lower heart rates and body temperature when compared to normal mice. They also have some other anomalies in heart function. The heart rate and temperature do not rise if the mice's thyroid hormone levels are increased. The disrupted mice do not display any evidence of thyroid hormone resistance.

Mice that have their TRb gene disrupted on the other hand display significant symptoms. They are deaf, display a distinct resistance to thyroid hormone and consequently have many symptoms of chronic hypothyroidism.

These studies indicate that heart function is more sensitive to the reaction of thyroid hormone with TRa whereas the significant metabolic effects are more sensitive to the reaction of thyroid hormone with TRb. The research group therefore developed a compound similar to thyroid hormone, but which reacts much more strongly with TRb than with TRa in the hope that it would increase the metabolic rate without over stimulating the heart.

Their results appear to validate their approach. The compound, KB-141, when given to obese monkeys, caused them to lose 7% of their body weight in 7 days without any change in their diet and with no adverse cardiac effects.

The researchers compared the effects of T₃ on normal mice and mice with no TRa receptors with the effects of KB-141 on these two groups of mice and also the effects of KB-141 on normal rats and monkeys. The overall effects were:

• T₃ had a much greater effect on increasing heart rate in normal mice than in the TRa deficient mice.
• T₃ increased metabolic rate as measured by whole body oxygen consumption in both types of mice, but the increase in the TRa deficient mice was only half that in the normal mice. (this suggests that both thyroid receptors have an impact on the metabolic rate).
• T₃ had an equivalent effect on lowering cholesterol in both types of mice.
• KB-141 increased metabolism with a 17 fold selectivity over the increase in heart rate in normal mice. In other words it was 17 times more effective at raising the metabolism than at raising the heart rate.
• KB-141 increased metabolism with an 11 fold selectivity in the TRa deficient mice.
• KB-141 increased metabolism with a 10 fold selectivity and lowered cholesterol with a 27 fold selectivity in rats.
• KB-141 produced significant cholesterol, lipoprotein (a) and body weight reduction in monkeys with no effect on heart rate.

Whilst this research was aimed at a treatment for obesity, it seems reasonable that a compound like KB-141 might also be useful for treating hypothyroid patients who also have heart conditions. It may also prove suitable for use in combination with T₄ therapy for a wider group of hypothyroid patients.

The research has only just begun so it will be some years before we know whether KB-141 offers real benefits in humans.

References

1. Gary J Grover and others, "Selective thyroid hormone receptor b activation: A strategy for reduction of weight, cholesterol and lipoprotein(a) with reduced cardiovascular liability", Proceedings of the National Academy of Science, 19 August 2003; 100(17):10067-72. http://www.pnas.org/cgi/content/abstract/100/17/10067
2. Scientif American review of the article. http://www.sciam.com/article.cfm?articleID=0007C2AD-A353-1F25-8D4A80A84189EEDF
3. Thyroid Disease Manager Chapter 3D. http://www.thyroidmanager.org/Chapter3/3d-frame.htm

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