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Discovery illuminates how thy-

roid hormone 'dims' me-
tabolism
Date: February 17, 2021

Source: University of Pennsylvania School of

Medicine
Summary: Basic biology finding on thyroid hor‐
mone function could lead to new treat‐
ments for obesity, diabetes and related
disorders

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FULL STORY

It has been known for some time that the

thyroid gland is a strong regulator of the
body's metabolism, making it key to many
health conditions. But the molecular details
of how thyroid hormone acts on cells in the
body have never been fully understood.
Now researchers at the Perelman School of
Medicine at the University of Pennsylvania
have taken a big step toward the resolution
of this mystery by showing that it doesn't
operate as a straight on/off switch, but more
like a dimmer.
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Biologists have known that, in cells where thyroid hor‐

mone acts to regulate metabolism, it operates in the
cell nucleus, increasing the activity of some genes and
decreasing the activity of others. The details of how
the hormone controls gene activity have been mostly
unknown, due to technical hurdles that have made it
difficult to study them. The Penn Medicine researchers,
who report their discovery today in Genes and Devel‐
opment, were able to overcome many of these techni‐
cal hurdles to provide a much clearer picture of thyroid
hormone's basic mechanisms of action -- in the
process overturning other prominent models of these
mechanisms.

"We were able in this study to show that thyroid hor‐

mone doesn't just turn things on or off, as the canoni‐
cal model suggests, but instead more subtly shifts the
balance between the repression and enhancement of
gene activity," said principal investigator Mitchell Lazar,
MD, PhD, Ware professor of Diabetes and Metabolic
Diseases, and the director of the Institute for Diabetes,
Obesity and Metabolism, at Penn Medicine. "Yet, as
people with hypothyroidism know, the lack of thyroid
hormone can have profound effects on the body."

Diseases of the thyroid gland, including hypothy‐

roidism, hyperthyroidism, and goiter, have been de‐
scribed for as long as there have been doctors. The
thyroid-produced molecule thyroxine, the chemical
precursor to the main active form of thyroid hormone,
was identified in 1914.

Endocrinologists also have long recognized that thy‐

roid hormone is an essential metabolism-enhancing
regulator whose insufficiency can lead not only to obvi‐
ous thyroid diseases but also to weight gain and relat‐
ed metabolic problems including diabetes, high cho‐
lesterol, and fatty liver disease. Thus, the hormone's
mechanism of action, if understood, could be a drug
target of enormous value for medicine.

But although scientists have known for almost 40

years that thyroid hormone acts in the cell nucleus to
control gene activity by binding itself to special pro‐
teins called thyroid hormone receptors, how it all
works has remained an enigma -- largely because the
interactions of thyroid hormone and its receptors have
been difficult to study. Among other challenges, the
receptors normally are produced in relatively tiny quan‐
tities in cells, and scientists have lacked a good way to
mark their binding sites on DNA -- and to see how
these binding sites differ when thyroid hormone is
present.

In the new study, for which Yehuda Shabtai, PhD, a

postdoctoral researcher in the Lazar lab, served as
lead author, the researchers developed a mouse model
in which a special tag was added to TRβ, the main thy‐
roid hormone receptor in the liver -- where some of
thyroid hormone's most important metabolic effects
occur. The researchers used this tag for marking the
thousands of locations on DNA where TRβ binds, both
in a condition when thyroid hormone was present and
could bind to TRβ and also when the hormone was
largely absent. With these and other experiments, the
team provided strong evidence that thyroid hormone
works with TRβ in an unexpectedly subtle way.

When it binds to a given site on coiled DNA in the nu‐

cleus, TRβ will enhance or repress the activity of a
nearby gene or genes. To achieve this, it forms com‐
plexes with other proteins called co-activators and co-
repressors. The researchers showed when thyroid hor‐
mone is bound to TRβ, it can shift the balance of these
associated co-regulator proteins in favor of more gene
activation at some sites, and more gene repression at
others. This is in contrast to prior models of thyroid
hormone / TRβ function in which thyroid hormone has
a more absolute, switch-like effect on gene activity.

The researchers acknowledge that more work needs to

be done to elucidate why thyroid hormone's binding to
TRβ lowers gene activity at some sites on DNA, and
increases gene activity at other sites. But they see the
new findings as a significant advance in understanding
a basic process in biology -- a process that future
medicines may be able to target precisely to treat a
variety of metabolic diseases.

Their work was supported by the National Institute of

Diabetes and Digestive and Kidney Diseases
(DK43806, DK19525) and the Cox Institute for Medical
Research.

Story Source:

Materials provided by University of Pennsylvania

School of Medicine. Note: Content may be edited for
style and length.

Journal Reference:

1. Yehuda Shabtai, Nagaswaroop K. Nagaraj, Kirill

Batmanov, Young-Wook Cho, Yuxia Guan, Chunjie
Jiang, Jarrett Remsberg, Douglas Forrest, Mitchell
A. Lazar. A coregulator shift, rather than the
canonical switch, underlies thyroid hormone
action in the liver. Genes & Development, 2021;
DOI: 10.1101/gad.345686.120

Cite This Page:

MLA APA Chicago

University of Pennsylvania School of Medicine. "Dis‐

covery illuminates how thyroid hormone 'dims' me‐
tabolism." ScienceDaily. ScienceDaily, 17 February
2021. <www.sciencedaily.com/releas‐
es/2021/02/210217175202.htm>.

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