The rockefeller university

Brown fat cells with mitochondria labeled in magenta. (Image acquired on a CSR Biotech Cell Xtreme microscope on demo at the BIRC)

Scientists have discovered that the drug losartan, commonly prescribed for high blood pressure, boosts brown adipose tissue activity in mice, enhancing their metabolism. This indicates that repurposing losartan—an angiotensin receptor blocker (ARB) 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, reported for the first time in this study, psychiatric health.

In a paper published in Nature, researchers in Rockefeller University’s Laboratory of Molecular Metabolism, led by Paul Cohen and joined by MSKCC researchers Heiko Schöder and Daniel Lafontaine, found that across all diagnoses, those conditions were less prevalent in individuals with brown fat.

The researchers initially discovered the connection between brown fat and ARBs through an analysis of medical records from 100,000 patients at Memorial Sloan Kettering Cancer Center (MSKCC). The work builds on discoveries Cohen’s lab made in 2021 in which they characterized roughly 50,000 MSKCC patients, finding that people with more brown fat had significantly lower odds of cardiometabolic diseases, including coronary artery disease and type II diabetes.

“We only looked for a few diagnostic codes in that study, mainly focusing on cardiovascular disease since that’s what this tissue has historically been associated with,” says Cohen. “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.”

AI powered

The current study followed a reverse translational approach that seeks to uncover the molecular underpinnings of clinical observations, a method the Cohen lab has often used to discover insights into the role of brown fat in the past. Here, the researchers analyzed PET/CT scans from over 100,000 patients were performed as part of their cancer surveillance. They then focused on the scans that had detected the presence of BAT, which is located in six regions of the body, including the neck, armpit, and surrounding organs like the heart and kidneys.

First author Nicolás Gómez-Banoy, an endocrinologist and instructor in clinical investigation in Cohen’s lab, applied a machine learning tool developed by colleagues at MSKCC to quantify the total degree of BAT activity in each patient, as well as the activity in each of the six anatomical regions.

Gómez-Banoy found that, in addition to having brown fat or not, the location of BAT was important, since higher brown fat activity in certain regions seemed to have greater influence for specific diseases.

“For example, the axillary, or armpit, area was linked to a decreased risk of high blood pressure compared to other regions,” he says. “But overall, patients with brown fat have better glycemic parameters, lipid profiles, and echocardiographic indices, as well as lower inflammatory markers.”

Further analyses revealed that patients taking ARBs had a higher presence of brown fat in their scans. To examine the relationship more closely, the researchers designed experiments to test the impact of losartan in cultured brown fat cells, and demonstrated that this drug directly increased their metabolic activity. They also learned that the molecular interactions by which losartan induced these effects were distinct 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,” says Gómez-Banoy. “That way you would be able to stimulate brown fat in people with normal blood pressure.”

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.

Mind and body

The team also uncovered links to mental health, including a lower incidence of anxiety and depression in patients with the presence of brown fat. “We know that metabolically healthy people tend to have lower incidence of psychiatric diseases, so it could be that having brown fat makes you more metabolically healthy, and this correlates with fewer psychiatric issues,” says Gómez-Banoy. Conversely, they found that SSRIs, commonly prescribed for depression, had a dampening effect on brown fat activity.

The findings open several new research paths, including studying the genetics of people with high levels of BAT, the connection to anxiety and depression, and potential downsides, including higher rates of osteoporosis and skin diseases in people with BAT. There are also drugs beyond losartan to look into.

“There were plenty of other medications associated with brown fat activity in our large cohort,” Cohen notes. “This is just a start.”