Gladstone scientists identify existing drug that increases ‘good’ fat mass and function

The already-approved anticancer drug prevented weight gain in animal model, causing the mice to burn more calories, and may have implications in obesity and diabetes treatment

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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.

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