Metabolic

Questions and Solutions: Brown fats linked to raised cardiovascular and metabolic well being

F.At has long been demonized as a sign of poor health, but the relationship between fat and well-being is not that sharp and dry. People have many different types of fat – including white, beige, and brown adipose tissue – not all of which expand our waistlines. While white fat stores calories as energy for leaner times, brown fat is fortified with mitochondria, which burn lipids and convert chemical energy into heat when our body temperature drops.

Paul Cohen

Zach Veilleux / Rockefeller University

Compared to white fat that accumulates along the midsection and hips, brown fat tends to be deeper in the body, making it difficult to study. Until 2009, scientists weren’t even sure whether adults would retain their brown fat beyond childhood. As a result, very little is known about the environmental and genetic factors that affect brown fat or its function in the body. With the advent of better imaging techniques, scientists have begun studying the possible role of brown fat in alleviating disease.

Paul Cohen, a physician-scientist at Rockefeller University, spoke to The Scientist about the challenges of studying this lesser-known tissue. His team published the results of a January 4 study in Nature Medicine that collected the largest data set ever created to examine the relationship between brown fat and health in humans. Cohen and colleagues analyzed around 130,000 individual PET-CT scans of more than 52,000 patients at Memorial Sloan Kettering Cancer Center and showed that those with more brown fat were less likely to suffer from cardiometabolic disorders such as high blood pressure, type 2 diabetes, and coronary artery disease , the leading cause of death in the US. These results were particularly pronounced in people with higher BMI and opened up new avenues for the prevention and treatment of diseases related to obesity.

The Scientist: Why did you want to investigate 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 to defend against hyperthermia. The idea was that brown fat is present at birth and. . . that brown fat atrophies as infants get older. A number of publications from 2009 reported that adult humans actually have brown fat and that it is cold inducible and functional, which means it can take up radioactively labeled glucose [for PET-CT imaging]. And this work met with enormous enthusiasm among basic and translation researchers.

In humans, we can see brown fat with a radiological scan. . . this measures the uptake of radiolabelled glucose [in different tissues]. Because these tests use radiation and require the administration of a radiotracer, it is not possible to conduct research studies on large numbers of subjects. Most of the studies have not aimed at exploring the links between brown fat and various diseases.

These associations make the really exciting idea that the presence of brown fat may protect against these obesity-related diseases.

– Paul Cohen, The Rockefeller University

We were interested in this question because in my laboratory we were studying brown fat in mouse models and cells and really wanted to know more about its human relevance. We took advantage of the fact that we are across from Sloan Kettering, which is a major cancer hospital. They’re doing thousands and thousands of scans there because [these] Scans are commonly used to diagnose or track cancer progression. It is their practice to always point out the presence of brown fat, as the tissues that take up radiolabelled glucose could otherwise be misunderstood as cancer. That way we were able to compile the massive data set that we believe is by far the largest reported today. There we could have the patient’s brown fat status and then link their status to all other information in their electronic health records. These associations make the really exciting idea that the presence of brown fat may protect against these obesity-related diseases.

TS: Why do you think the presence of brown fat correlates with a lower incidence of cardiometabolic and cardiovascular disease?

PC: We are currently focusing on a few different hypotheses. One is that maybe the presence or amount of brown fat affects the distribution of white fat, [affecting] the relative amounts of visceral or abdominal fat – which is more pathogenic – compared to subcutaneous fat, which is less harmful. Another possibility is that brown fat uses up energy and therefore acts as a sink for a number of metabolites that could be toxic. And then a third possibility is the endocrine function of brown fat. We know a lot about endocrine hormones from white fat such as leptin and adiponectin. Now there is evidence that brown fat is also an important endocrine organ.

Many of these diseases, such as coronary artery disease, heart failure and high blood pressure, are regulated by very complex physiological systems and affect several organs. So the connection between these and brown fat at least increases the possibility that they could be regulated by endocrine signals.

TS:: They found that the presence of brown fat appeared to offer some protection against metabolic and cardiovascular diseases, especially in people with higher BMI. Can you explain this relationship in a little more detail?

PC: What we’ve been doing here is asking, “What’s the relationship between brown fat and increasing BMI?” For example, if you take type 2 diabetes, which I think our data has been most striking, it is well known that the risk and prevalence of type 2 diabetes increases as people switch from normal weight to overweight to obesity . What we found, however, is that across all three weight strata, people with brown fat had a significantly lower prevalence of type 2 diabetes than people without brown fat. In fact, people who are obese and had brown fat had only a slightly higher prevalence of type 2 diabetes than people with a normal BMI who did not have brown fat.

These associations make the really exciting idea that the presence of brown fat may protect against these obesity-related diseases. And if so, we can devise pharmacological approaches or interventions to activate or increase the amount of brown fat a person has. This could be a way to either treat or prevent some of these diseases.

Using PET-CT scans, scientists can visualize a patient’s brown fat. The motif on the left has a larger proportion of the tissue along the neck and spine.

Zach Veilleux / Rockefeller University

T.S: How could brown fat be used as a therapy for cardiometabolic diseases?

PC: Currently the best way to activate or increase brown fat. . . is with exposure to cold. Of course, the use of cold exposure as a treatment is unlikely to be what many patients will be excited about. So many people are trying to understand more about the basic molecular and biochemical pathways involved in regulating or activating brown fat to see if these components can be targeted pharmacologically.

There is a clinically approved drug called mirabegron that is used to treat overactive bladder. However, research studies have been conducted. . . this has shown that administering mirabegron to subjects can activate brown fat. If it turns out that the benefits of brown fat are primarily mediated by an endocrine hormone released by brown fat, then the path to this approach is to identify the hormone, learn more about how it works, and target it.

TS:: You said there are a lot of groups working on this, but I’m excited to see what your next plan is based on these findings.

PC: We are very excited about the genetics of brown fat. We know there are environmental factors – things like age, gender, BMI – but we’re taking different approaches to see if we can identify genetic variants associated with exceptionally high levels of brown fat. Once we identify these variants, we can study them in cells and animal models to see how they lead to this phenotype. And I think that has all possible possibilities.

T. Becher et al., “Brown adipose tissue is linked to cardiometabolic health”. Natural medicine, doi: 10.1038 / s41591-020-1126-7, 2021.

Editor’s note: The interview has been edited for brevity.

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