In a National Institutes of Health (NIH)-funded study, scientists have demonstrated that the drug losartan, commonly prescribed for high blood pressure, boosts brown adipose tissue activity in mice, enhancing their metabolism. Researchers initially discovered the connection between brown fat and the drug class to which losartan belongs, known as angiotensin receptor blockers (ARBs), through an analysis of over 100,000 patients. This indicates that repurposing a widely used drug, with a well-known safety profile, may be a clinically viable method of stimulating brown fat, which has been linked to improved cardiovascular health and, identified for the first time in this study, psychiatric health.
"The unique reverse translational approach of this study, enabled by large clinical datasets and next-generation analytical tools, provides a much-needed clinical rationale for exploring brown adipose tissue as a therapeutic target in humans across a spectrum of diseases," said Griffin P. Rodgers, M.D., director of NIH's National Institute of Diabetes and Digestive and Kidney Disease (NIDDK).
While white fat stores energy in the body, brown fat burns through it to produce heat. Coincidentally, a specific kind of PET/CT imaging often used in clinical oncology can measure this process. By assessing these kinds of images and medical records from more than 50,000 patients being treated for cancer, a research team led by Paul Cohen, M.D., Ph.D., at Rockefeller University recently drew connections (link is external) between brown fat and reduced prevalence of cardiovascular and metabolic disease.
"We only looked for a few diagnostic codes before, mainly focusing on cardiovascular disease since that's what this tissue has historically been associated with," Cohen said. "The scope of this new analysis is far more expansive. We doubled our number of patients and considered more than 500 codes, which allowed us to unearth many new insights."
Cohen, joined by Memorial Sloan Kettering Cancer Center researchers Heiko Schöder, M.D., and Daniel Lafontaine, used artificial intelligence techniques to identify brown fat associations among more than 100,000 patients who received PET/CT imaging for cancer.
The authors built on top of previously known links and have now demonstrated that, in addition to having brown fat or not, a higher degree of brown fat activity is connected to more cardiometabolic benefits. They also discerned these associations across the body's six brown fat depots, with increased activity in the armpit depot being most strongly tied to cardiometabolic health.
They uncovered some new connections as well, including a lower incidence of anxiety and depression in patients with greater brown fat presence. Another signal that stood out was the higher levels of brown fat activity among patients taking ARBs.
To examine the relationship between ARBs and brown fat more closely, the researchers tested the impact of losartan in brown fat cells, finding that the drug directly increased their metabolic activity. They also learned that the molecular interactions by which losartan induced these effects were separate from the mechanisms underpinning its more well-known blood-pressure lowering properties.
"The fact that its different effects are mediated by different molecular pathways is advantageous, since it means we could potentially isolate them in future therapies. That way you would be able to stimulate brown fat in people with normal blood pressure," said first author Nicolás Gómez-Banoy, M.D., an instructor of clinical investigation at Rockefeller and an endocrinologist at Weill Cornell Medicine.
Healthy mice treated with losartan also exhibited many indicators of enhanced metabolism, such as increased energy expenditure, oxygen consumption, and carbon dioxide production, all while maintaining a steady body weight.
These results help form a basis for further investigation into inducing brown fat activity in humans. Depending on the outcome of such potential experiments, future studies could go in many different directions. However, no matter the result, researchers are not short on options.
"There were plenty of other medications associated with brown fat activity in our large cohort. This is just a start," Cohen said.
NIH supported this research through NIDDK grant DP1DK139983, National Cancer Institute (NCI) grant P30CA008748, National Institute of General Medical Sciences (NIGMS) grant T32GM152349, and National Center for Advancing Translational Sciences (NCATS) grant UL1TR001866.
