Fat has long been demonized as a sign of poor health, but the relationship between fat and well-being is not so cut and dry. Humans have many different types of fat—including white, beige, and brown adipose tissue—not all of which widen our waistlines. While white fat stores calories as energy for leaner times, brown fat is enriched with mitochondria that burn up lipids, converting chemical energy into heat when our body temperature drops.
Compared to white fat, which collects along the midsection and hips, brown fat tends to reside deeper in the body, making it more difficult to study. Until 2009, scientists weren’t even sure that adults retained their brown fat beyond childhood, and as a result, very little is known about the environmental and genetic factors that influence brown fat or its function in the body. With the advent of better imaging techniques, scientists have begun to probe brown fat’s possible role in mitigating disease.
Paul Cohen, a physician-scientist at the Rockefeller University, spoke to The Scientist about the challenges of studying this lesser-known tissue. His team published the results of a study January 4 in Nature Medicine in which they amassed the largest dataset ever produced to study the relationship between brown fat and health in humans. By analyzing roughly 130,000 individual PET-CT scans from more than 52,000 patients at Memorial Sloan Kettering Cancer Center, Cohen and his colleagues showed that individuals with more brown fat are less likely to suffer from cardiometabolic diseases such as hypertension, type 2 diabetes, and coronary artery disease, the leading cause of death in the US. These findings were especially pronounced in people with higher BMIs, opening up new possibilities for preventing and treating obesity-related diseases.
The Scientist: What made you want to examine this link between brown fat and cardiometabolic health?
Paul Cohen: For a long time, people felt that brown fat was really only relevant in small mammals and newborn humans as a way to defend against hyperthermia. The idea was that brown fat is present at birth and . . . that the brown fat atrophies as infants get older. A series of papers in 2009 reported that adult humans do in fact have brown fat and that it is cold-inducible and functional, meaning it can take up radio labeled glucose [for PET-CT imaging]. And those papers really generated an enormous amount of enthusiasm among basic and translational researchers.
In humans, the way that we detect brown fat is with a radiology scan . . . that measures the uptake of radio labeled glucose [in different tissues]. Because these tests use radiation and require administration of a radiotracer, it’s not feasible to do research studies in large numbers of subjects. Most of the studies haven’t been powered to look more deeply at associations between brown fat and different medical conditions.
These associations are raising the really exciting notion that perhaps the presence of brown fat protects against these obesity-associated diseases.—Paul Cohen, The Rockefeller University
We were interested in that question because we study brown fat in mouse models and cells in my lab, and we really wanted to know more about its human relevance. We took advantage of the fact that we’re across the road from Sloan Kettering, which is a major cancer hospital. They do thousands and thousands of scans there because [these] scans are commonly used to diagnose or track the progression of cancer. It is their practice to always comment on the presence of brown fat because the tissues that take up radio labeled glucose could otherwise be misconstrued as a cancer. That allowed us to assemble the massive dataset, that we believe is by far the largest reported today, where we could have patients’ brown fat status and then link their status to all of the other information in their electronic health records. These associations are raising the really exciting notion that perhaps the presence of brown fat protects against these obesity-associated diseases.
TS: Why do you think that the presence of brown fat is correlated with lower incidences of cardiometabolic and cardiovascular disease?
PC: We’re currently focused on a few different hypotheses. One is that perhaps the presence or amount of brown fat influences the distribution of white fat, [affecting] the relative amounts of visceral or belly fat—which is more pathogenic—versus subcutaneous fat, which is less deleterious. Another possibility is that brown fat consumes energy, and therefore acts as a sink for a number of metabolites that could be toxic. And then a third possibility is the endocrine functions of brown fat. We know a lot about endocrine hormones made by white fat, like leptin and adiponectin. Now, there’s emerging evidence that brown fat is also an important endocrine organ.
Many of these diseases, like coronary artery disease, congestive heart failure, and hypertension, are regulated by very complex physiological systems and involve multiple organs. So the link between those and brown fat at least raises the possibility that they could be regulated by endocrine signals.
TS: You found that the presence of brown fat seemed to confer some amount of protection against metabolic and cardiovascular disease particularly in people with higher BMIs. Can you explain that relationship a bit more?
PC: What we did here is ask, ‘what is the relationship between brown fat and increasing BMI?’ If you take type two diabetes, for example, where I think our data were most striking, it’s very well known that as people move from normal weight to overweight to obese, the risk and prevalence of type two diabetes goes up. What we found though is that in all three weight strata, people who had brown fat had a significantly lower prevalence of type two diabetes than people who did not have brown fat. And in fact, people who are obese and had brown fat had a prevalence of type two diabetes that was only slightly higher than people with a normal BMI who did not have brown fat.
These associations are raising the really exciting notion that perhaps the presence of brown fat protects against these obesity-associated diseases. And if that is true, then we can develop pharmacological approaches or interventions to activate or increase the amount of brown fat that a person has. That might be a way to either treat or help prevent some of these diseases.
TS: How could brown fat be harnessed as a therapy for cardiometabolic disease?
PC: Currently, the best way to activate or increase brown fat . . . is with cold exposure. Of course, using cold exposure as a treatment is probably not something a lot of patients are going to be enthusiastic about. So many people are trying to understand more about the basic molecular and biochemical pathways that are involved in regulating or activating brown fat to see if those components can be targeted pharmacologically.
There is a drug that’s clinically approved called mirabegron that is used to treat overactive bladder. But there have been research studies . . . that have shown that administering mirabegron to subjects can activate brown fat. If it turns out that the benefits of brown fat are mainly conveyed by an endocrine hormone released by brown fat, then the way to approach that would be to identify the hormone, learn more about how it acts, and target that specifically.
TS: You said there are many groups working on that, but I’m curious to know what your next plan is based off of these findings.
PC: We’re very excited about the genetics of brown fat. We know that there are environmental factors—things like age, gender, BMI—but we are taking a number of different approaches to try and see if we can identify genetic variants that are associated with exceptionally high amounts of brown fat. If we identify those variants, we can then study them in cells and animal models to work out how they lead to this phenotype. And I think that has all sorts of possibilities.
T. Becher et al., “Brown adipose tissue is associated with cardiometabolic health,” Nature Medicine, doi:10.1038/s41591-020-1126-7, 2021.
Editor’s note: The interview was edited for brevity.