Thyroid hormone appears to regulate metabolism by acting as a ‘dimmer switch’ as opposed to an ‘on/off’ switch, as reported by a new study from the University of Pennsylvania.
The thyroid hormone has long been known to be an important controller of the body’s metabolism, as well development, but how exactly this is achieved remains something of a mystery. Part of this problem was that the thyroid hormone worked inside the nucleus, activating some genes and deactivating others. Being able to observe this process has been extremely challenging.
“We were able in this study to show that thyroid hormone doesn’t just turn things on or off, as the canonical model suggests, but instead more subtly shifts the balance between the repression and enhancement of gene activity,” said principal investigator Mitchell Lazar, MD, PhD, at Penn Medicine. “Yet, as people with hypothyroidism know, the lack of thyroid hormone can have profound effects on the body.”
Knowing how thyroid hormone regulates the body’s metabolism would be a great boon for new drug development, especially to tackle obesity. For four decades, scientists have known that thyroid hormone acts on thyroid hormone receptors, but these special proteins exist in small quantities and marking where they are on DNA has proven difficult.
In the new study, the researchers developed a mouse model in which a special tag was added to TRβ, the main thyroid hormone receptor in the liver, which is where important metabolic effects of thyroid hormone occur. With this tag, they marked the thousands of locations on DNA where TRβ binds, both in states when thyroid hormone was present and could bind to TRβ and also when no hormone was present. In this way, the team came up with strong evidence that shows the unexpectedly subtle manner in which thyroid hormone works with TRβ.
When it binds to a DNA site, TRβ will promote or suppress nearby gene activity by forming complexes with other proteins called co-activators and co-repressors. When thyroid hormone is bound to TRβ, it can alter the balance of these co-regulator proteins towards more gene activation at some sites, and more gene repression at others. Prior models of thyroid hormone / TRβ function in which thyroid hormone has a more absolute, switch-like effect on gene activity.
The researchers acknowledged that more work is needed to discover just how genes are activated or repressed at the sites. However, this is a significant advancement towards treatments which can directly influence the body’s metabolism.
Source: Medical Xpress
