Drug Turns on Brown Fat and Burns Calories in People
Clinical study of Beta3-adrenergic receptor drug points to potential benefits in obesity and diabetes
BOSTON – (January 6, 2015) – In an early phase clinical trial led by Joslin Diabetes Center researchers, an oral drug approved for treating incontinence successfully activated brown fat – a form of fat that can help to expend energy. At peak effect, the drug boosted energy consumption by more than a tenth in the trial volunteers, suggesting that it might help in losing weight.
Aaron Cypess, M.D., Ph.D., an investigator at the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health in Bethesda, MD.
Unlike the far more common white fat, brown fat can speed up metabolism in people who are subjected to cold. Scientists had long known that this form of fat is present in babies and young children, and scientists from Joslin and other institutions demonstrated in 2009 that these cells can be found in adults as well. Experiments in animals revealed that the cells can be activated by various agents, among them drugs that link to a protein on the cell surface called a Beta3-adrenergic receptor.
In the clinical study, the Joslin researchers tested a Beta3-adrenergic receptor drug called mirabegron, approved for improving bladder control by the U.S. Food and Drug Administration (FDA) in 2012. (Known commercially as Myrbetriq, the drug is offered by Astellas Pharma, which was not connected with the brown fat study.)
“We expected to see an increase in brown fat activity and an increased amount of calories being burned, because that’s what we'd seen with these drugs in animals,” says Aaron Cypess, M.D., Ph.D., lead author for a paper in the journal Cell Metabolism. “And that's what we found.”
However, no one should be tempted to use the drug for weight loss based on these preliminary findings, warns Cypess, who led the trial as an assistant investigator at Joslin and is now an investigator at the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health in Bethesda, MD.
Among the reasons for caution, the trial dosage was four times the level approved by the FDA for daily bladder treatment, and there are concerns that mirabegron may increase blood pressure and produce other potentially serious side effects.
The trial began by recruiting 12 healthy men with brown fat, which the researchers had already detected by chilling the men with a “cooling vest” full of cold water and scanning them via positron emission tomography/computer tomography (PET/CT) imaging. The men then were given either mirabegron or a placebo, scanned again, and tested for their energy consumption while at rest.
Earlier studies had revealed that there are two main forms of brown fat cells, including “classic” brown fat that is present at birth and “beige” fat that can be produced within white fat calls. Studies have indicated that brown fat is mostly localized around the neck and beige fat is mostly found in the shoulders, chest, and abdomen. Brown fat appeared in the expected locations among volunteers given the drug, although the imaging could not distinguish between the two types. “We also saw brown fat in places we didn’t even know there was brown fat,” Cypess remarks.
At its maximum effect, mirabegron increased the metabolic rate by more than 10%. “If the metabolic rate increase were maintained for a long enough period, you could start talking about potentially having an effect on weight loss,” Cypess says.
The trial was not designed to shed light on the question of whether the drug also can help to create new brown fat cells. “We know from animal studies that drugs that activate the Beta3-adrenergic receptor can substantially increase the amount of brown fat in the body,” he says. However, volunteers received only a single dose of mirabegron, since PET/CT scanning involves exposure to a small amount of radiation. (Cypess and other investigators are exploring whether magnetic resonance imaging, MRI, can provide a workable alternative for brown fat imaging that doesn’t pose this risk.)
Widespread interest in activating brown fat has been driven by its promise for weight loss, which could aid in treating obesity and related conditions such as type 2 diabetes. These cells also may offer other beneficial effects such as improved glucose metabolism, Cypess says.
Additionally, he points out, Beta3-adrenergic receptor agents activate white fat cells. “There’s evidence in both rodents and humans that if you stimulate white fat to break down and release its supply of stored fat, you may oxidize (burn up) and decrease the amount of white fat in the body, which has a metabolic benefit that is separate from whatever brown fat may be doing,” he says.
From a research perspective, these drugs may ease logistics for clinical studies on brown fat activation, which has required placing volunteers in cold rooms or cold vests. “Now, you don’t necessarily have to expose people to cold; you can give them a pill, which makes it much easier to study the tissue,” Cypess notes.
Other Joslin contributors to the Cell Metabolism paper include Alessandro Doria, Skyler Kessler, Carla Roberts-Toler and Lauren Weiner. Contributions also came from Jeffrey English, Elisa Franquet and Gerald Kolodny of Beth Israel Deaconess Medical Center; Peter Kahn of Albert Einstein College of Medicine; and Kelly Chatman and Sunia Trauger of Harvard University.
This work was supported by National Institutes of Health (NIH) grants K23 DK081604, P30 DK036836, and the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); the Fundación Alfonso Martín Escudero; and the Clinical Translational Science Award UL1RR025758 to Harvard University and BIDMC from the National Center for Research Resources (NCRR).
The content of this press release is the sole responsibility of the authors and does not necessarily represent the official views of NIH.
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To request an interview with Dr. Cypess, contact Krysten Carrera at Krysten.firstname.lastname@example.org.