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Gladstone scientists identify existing drug that increases ‘good’ fat mass and function
01-24-2017
EDIT CONNECT
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SAN FRANCISCO—Scientists at
the Gladstone Institutes say that they have identified an FDA-approved drug that “can create
the elusive and beneficial brown fat,” according to a Gladstone news release.
Brown fat is distinct from the more
common—and more commonly known—white fat, which stores energy. The difference with brown fat is that it helps the body burn energy through heat,
Gladstone explained. Infants are born with small amounts of brown fat, but as they age, most of it disappears. In fact, for a long while, it was thought that
adults had no brown fat, though it was eventually determined that we do have small amounts of it in our bodies. In adults, people with higher amounts of
brown fat have lower body mass—according to Gladstone, increasing brown fat by as little as 50 grams could lead up to a 10- to 20-pound weight loss in
a single year.
In the new study, published in Cell Reports under the title “Brown Adipogenic Reprogramming Induced by a Small Molecule,”
the researchers note that Mice treated with the drug—the anticancer compound bexarotene—had more brown fat, faster metabolisms and less body
weight gain, even after being fed a high-calorie diet. The researchers say the technique, which uses cellular reprogramming, could be a new way to combat
obesity and type 2 diabetes.
“Introducing brown fat is an exciting new approach to treating obesity and
associated metabolic diseases, such as diabetes,” said study first author Dr. Baoming Nie, a former postdoctoral scholar at Gladstone. “All
current weight loss drugs control appetite, and there is nothing on the market that targets energy expenditure. If we can create additional stores of brown
fat and boost its function in the body, we could burn off the energy stored in white fat more easily.”
So,
how were the researchers able to create brown fat? Well, scientists in the laboratory of Gladstone senior investigator Dr. Sheng Ding, used cellular
reprogramming to convert muscle precursor cells and white fat cells into brown fat cells. More the specific point of their systematic work, the researchers
tested 20,000 chemicals until they found one that changed the identity of the cells most effectively. The “winner” was Bex, which reportedly
surprised the scientists, as it targets a protein that was not previously shown to be involved in generating brown fat.
According to Gladstone, Bex acts on a “master regulator” protein called retinoid X receptor (RXR), which controls a network of other
cellular proteins. Activating RXR triggered a cascade of changes in muscle precursor cells and white fat that ultimately converted them into brown fat-like
cells. Specifically, when RXR was stimulated by Bex, it turned on genes needed to produce brown fat and turned off genes linked to white fat or
muscle.
To test how well Bex controls body weight, the scientists fed mice a high-calorie diet for four weeks, but
they only treated half of the mice with the drug. The mice that were given Bex had more brown fat, burned more calories, had less body fat and gained less
weight than mice that were fed the same diet but were not given the drug.
“We’re very excited about
the prospect of using a drug to generate brown fat in the body,” said Ding. “However, while Bex is very effective at creating brown fat cells, it
is not a very specific drug, and there are several potential side effects that may arise from taking it. Our next task is to develop a safer, more targeted
drug that only affects genes involved in creating brown fat.”
In a bit of symmetry, it was almost exactly
two years previous to this Gladstone news that a National Institutes of Health (NIH) researcher and
colleagues had found another existing drug—mirabegron, which had already been approved by the FDA to treat overactive bladder—that activated
brown fat to increase metabolism.
As the NIH noted at the time, brown fat cells have β3-adrenergic receptors
on their surface. These protein receptors span the cell membrane and serve as gatekeepers to transmit signals between the outside and inside of cells.
Several other tissues also have β3-adrenergic receptors, including white fat and the bladder. As it turned out, mirabegron activates these
receptors.
Dr. Aaron Cypess—then at NIH’s National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK)—had done this work in his previous position at the Joslin Diabetes Center in Boston along with colleagues, wherein they examined
whether this drug might activate β3-adrenergic receptors on brown fat cells to increase metabolism in humans. The research was supported in part by
NIDDK and by NIH’s National Center for Research Resources and National Center for Advancing Translational Sciences. Results were published in January
2015 in Cell Metabolism.
The team screened 15 healthy, lean men for participation in the study. Of these,
12 showed detectable levels of brown fat. These men, average age 22 years, underwent two additional imaging tests on two different days. For one test, each
took a single 200-mg dose of mirabegron. For the other test, each received a placebo.
Several hours after taking
the drug or placebo, participants received infusions of a traceable form of glucose. The researchers found that participants had increased glucose uptake in
several tissues, including brown fat, after taking mirabegron and that the drug increased brown fat metabolic activity. Resting metabolic rate also rose by
an average of 203 calories per day. The increase in metabolic rate was associated with the increase in brown fat activity.
The researchers found that the drug caused an increase in resting heart rate and systolic blood pressure in the men, which are signs of
cardiovascular system stimulation. The drug also stimulated white fat.
“Brown adipose tissue, or brown fat,
produces β3-adrenergic receptor at levels higher than nearly every other organ in the body. We showed that a one-time dose of the drug mirabegron
stimulates human brown adipose tissue so that it consumes glucose and burns calories,” Cypess said.
The team
noted that since this was a small study conducted in healthy men, and the men only took the drug one time, much more research would be needed to determine
the safety and feasibility of activating this pathway as a way to increase energy expenditure.
Code: E01251703 Back |
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