White fat is that uncomely body substance we spend our lives trying to get rid of. We know it can be bad for our health, causing obesity and its cohort of related diseases. But scientists have recently discovered that adult human fat actually comes in other colors too. And this knowledge can unlock ways to reduce white fat and the problems it causes.
American scientist-physician Paul Cohen leads the Laboratory of Molecular Metabolism at the Rockefeller University in New York City. As a cardiologist, he sees many patients afflicted with the conditions that accompany obesity: diabetes, coronary artery disease, high cholesterol, hypertension, cancer.
Cohen recognizes how challenging it is for obese people to lose weight. That is why, since the discovery some years ago that the human body makes different types of fat, he has set a long-range goal. Rather than trying to reduce a person’s body weight, he studies the possibility of promoting healthier fat in the body to alleviate the burden of illness related to obesity. On the occasion of a recent talk he gave at the Champalimaud Centre for the Unknown, he explained his research to Ar Magazine.
Fat is not the amorphous white “goo” we commonly picture, is it?
You’re right. I think our view of fat – or adipose tissue – has really changed. A few decades ago, people viewed fat as a bag of cells that had developed to store extra energy, in the form of triester glycerol [triglycerides], that could then be mobilized in periods of starvation. But we now appreciate that fat is a complex and dynamic organ, like the lungs or the liver. It contains many different cell types that interact with one another, both within fat tissue and other tissues of the body.
We also know that there are different kinds of fat. There are white fat cells, which as I mentioned store energy, but there are also thermogenic fat cells, called thermogenic because they convert energy into heat. So, rather than storing energy, they actually dissipate, or burn, energy. And rather than being associated with disease, we think that these cells, which we call “brown” or “beige” fat cells, can actually help protect against obesity, diabetes and other associated diseases.
What is brown fat?
Brown fat has been known about for a very long time, and the idea is that it developed as a way to maintain body temperature. It was initially detected in newborn humans and small mammals, where it converts energy into heat and helps maintain body temperature in times of cold. Brown fat cells convert chemical energy into heat, and that heat is given off inside the body.
For a long time, people thought that brown fat was really only relevant in newborns and small mammals, but around 2009, a series of papers “rediscovered” brown fat in adult humans. And what they showed was that many adult humans have active brown fat. That really led to an explosion of studies looking at the function of brown fat in humans and mouse models.
What did these studies find?
In the course of those studies, what people came to realize was that mammals have two kinds of brown fat. There’s this developmentally pre-formed brown fat I’ve talked about, which is present at birth, but there are also so-called “inducible brown fat cells” – which we call “beige” fat cells. These beige fat cells exist as clusters within white fat depots and, in response to stimuli like cold exposure, exercice or certain drugs, they can become activated and turn on their thermogenic properties.
What is now of great interest – to us and other people in the field – is to understand what regulates the activity of brown and beige fat; we want to see whether it might be possible to convert unhealthy [white] fat into healthier [brown and beige] fat.
When was beige fat discovered?
The earliest study I am aware of describing inducible thermogenic fat was reported in the 1980’s in rats exposed to cold, but those cells were not labeled beige adipocytes [at the time]. It was only more recently, around 2011 or so, that people began to refocus on what we now call beige fat cells and found that they have many of the same properties as brown fat, but also certain differences. We now know that beige fat actually comes from a different developmental lineage from brown fat and that there are also some important biological differences between the two.
A lot of the initial work describing beige fat was done and elaborated by a postdoctoral trainee in Bruce Spiegelman’s lab, at the Dana Farber Cancer Institute in Boston, but many other investigators around the world have been involved as well.
Were you involved in this research from the beginning?
Yes. But I want to emphasize that neither the discovery of beige fat, nor its initial characterization, were my work. I participated in some of that work, but my main contributions came a little bit later.
Where are beige fat cells located in the body?
Most of what we know comes from mice and humans and there appear to be differences. Mouse brown fat is a discrete depot between the shoulders, where it mainly emerges as clusters of cells within subcutaneous white fat depots. Less is known in humans, but what we do know is that, in addition to clusters of beige fat cells within subcutaneous fat, there are also deposits of brown and beige fat along the neck and cervical spine. It remains to be seen, in humans, what the relative proportion and location of these cells are and what is their full physiological significance.
Does white fat turn into beige fat cells, or are there “dormant” beige fat cells inside the white fat from the start?
We still don’t fully know whether the activation of thermogenic fat occurs through the development of new thermogenic fat cells or whether it occurs through conversion of white fat cells. In the mouse, there seems to be evidence for both those phenomena, but in humans we don’t know the answer yet.
If that were also the case in humans, would it be possible to decrease our white body fat simply by living in cooler conditions (less central heating, sleeping without pyjamas)?
That is an interesting concept that people are beginning to investigate. If we put a mouse at 4ºC, it can live quite comfortably indefinitely, and one of the ways it does that is by activating its brown and beige fat. So people have wondered whether putting humans in the cold might be associated with the same benefits.
We know from some small studies in healthy human subjects that if you expose them to 4ºC for about six hours, and do a PET scan before and afterwards, you can see a dramatic induction of brown fat in their body. Other small studies in humans show that if you take humans with insulin resistance or diabetes and house them at a lower temperature – about 17ºC to 19ºC – you can get some transient improvements in insulin resistance, and if you then return these humans to 23ºC, some of these benefits go away. This certainly suggests that there could be such benefits, but they haven’t been shown in very large studies.
However, practically speaking, most humans are not going to be willing to subject themselves to cold [to reduce their white body fat]. But if we understood the molecular mechanisms, perhaps we could reproduce the effects of cold pharmacologically, without actual cold exposure.
Do populations that live under such conditions have more of this healthy fat?
There doesn’t seem to be any strong geographic variation, although prior to the studies from 2009 rediscovering brown fat in adults, there was a study from Scandinavia showing that people there who worked outdoors in the winter had more brown fat. That study didn’t get as much attention as it probably should. I think one reason why it’s difficult to address the geographic aspect is because in modern times humans live in thermal comfort. If we live in a hot climate we use air conditioning, if we live in a cold climate we wear sweaters and jackets and use heating. So our core temperature is not necessarily related to the ambient temperature.
Humans vary in their tolerance to cold. Does that have anything to do with the amount of brown or beige fat they have?
It may. There is some ongoing work in my lab to try and look at exactly what you ask. In the studies that have measured brown fat in humans, they used a PET scan to quantify brown fat mass and activity. And if you look at those data what you can see is that there are often individuals who have exceptionally high amounts of brown fat for their age and gender.
So the potential for producing beige fat could be genetically inherited?
Indeed, this raises the possibility that there could be genetic or environmental determinants controlling the activity of brown [and beige] fat. We’ve been trying to see whether individuals with exceptionally high amounts of brown fat have genetic variants or mutations that enable them to have such a high level of brown fat. If we could identify those variants, we could learn more about how this tissue is regulated.
Though we don’t know for sure, we predict that there is a genetically inherited component. For one, there are these extreme cases identified in studies, of people who have much more brown fat than others who come from the same location and the same environment.
Another line of evidence is a small clinical study that looked at brown fat in Caucasians versus Southeast Asians, and which found that Southeast Asians tended to have higher amounts of brown fat.
And last – and this is a really interesting story but it concerns only two individuals –, there is this person who calls himself “iceman”. His real name is Wim Hof and he has many of the world records for endurance to cold exposure. He has been studied and found to have a high amount of brown fat.
You might say: well of course he does, he exposes himself to cold. But it turns out he has an identical twin brother, who does not have the same hobby as him, and his brother also has a high amount of brown fat, at least for his age and gender. That’s only two individuals, but it at least suggests that there might be a genetic determinant involved.
Apart from cold temperatures, can certain substances induce beige fat activation or induce white fat to turn beige fat?
Release of adrenaline or noradrenaline may activate these cells. Other hormones have also been identified that appear to activate beige fat. Other investigators have shown that aerobic exercise can activate beige fat and there are probably a variety of other things that may do so as well. It’s a really active area of research.
You just mentioned adrenaline and noradrenaline, which are neurotransmitters. Does the nervous system play a role in the activation of beige fat cells?
There are a variety of physiological studies dating back ten or more years, mainly in mice, suggesting a role for the sympathetic nervous system [which is primarily concerned with stimulating the “fight-flight-or-freeze” response]. If you delete the so-called beta-adrenergic receptors – the receptors on the surface of cells which respond to activation from the sympathetic nervous system –, you lose the proper function of brown and beige fat. In addition, if you cut or pharmacologically abolish the innervation of adipose tissue, you also limit the ability to activate brown and beige fat.
In work we’ve done, we used three dimensional imaging to look at the innervation of adipose tissue in the mouse. And what we have found is that, in addition to large axons that enter the tissue, in subcutaneous fat we also see fine projections from these neurons that enter into the adipose tissue. We think it’s those projections that play a role in activating thermogenic fat cells. Moreover, the areas with the greatest density of fine projections have the greatest density of beige adipocytes.
What are you currently researching?
One of the things about fat cells, apart than just dealing with energy, is that they are really important endocrine cells: they can secrete metabolites and hormones that can either act locally or signal to other tissues in the body – and we think that those endocrine properties might play a very important role.
So one area we are very invested in trying to identify the full complement of proteins that can be made and secreted by different kinds of fat cells in different physiological contexts, because we believe that identifying those proteins can further help us understand how fat cells can contribute to protect against obesity and associated diseases.
To date, we have identified more than 800 different proteins secreted by the different kinds of fat cells. We are currently focusing on a couple of these proteins that haven’t been studied before to really try to solve what their physiological role is by making mouse knockout models, transgenic models, recombinant proteins, neutralizing antibodies. We hope that in the next year or so we can have that part of the project solved.
One of those proteins is predominantly made by visceral fat – the unhealthy fat – and its levels go up in obesity, so we think it might convey some of the adverse health effects of visceral fat. If this is true, then blocking the action of that protein might come with benefits. We’re also focused on a protein that’s made by brown and beige fat and is induced by cold, and we think it conveys some of the health benefits of brown and beige tissues. Enhancing the levels of that protein or figure out how it acts could also have therapeutic benefit.
Could this lead to future development of drugs against obesity, diabetes, cancer?
Well, that’s certainly my long range goal. I’m also a physician, a cardiologist, and so I see a lot of patients with diseases that come with obesity, like diabetes, coronary artery disease, high cholesterol, hypertension – and I recognize how challenging it is for people to lose weight. So my question is, might we be able to manipulate these pathways not to change a person’s body weight, but to create healthier fat, so that a person may not have the same burden of illness, even in the face of obesity?
Are you saying that, one day, it will be possible to be fat and healthy?
I don’t want to imply that being overweight or obese is healthy. But we do know that some people who are obese have diabetes, heart disease, cancer, liver disease, while others seem to be either unaffected or only affected by these health problems much later in life. I would say the majority are eventually affected, but there’s a sizeable amount who aren’t, or whose illness comes much later in life.
We want to know why that happens, and that’s of course a complicated question. It could be a combination of genetics, diet, physical activity. But one thing we know from human epidemiological studies is that one determinant factor is where an overweight or obese person stores his or her excess fat. We know from human studies that people who store their excess fat in a visceral location, around the internal organs – the so-called apple shaped – are much more likely to have health problems than people who store their fat in a subcutaneous or pear-shaped distribution.
All overweight and obese people have plenty of both visceral and subcutaneous fat, but it’s the relative proportion I’m talking about. People who have skinny arms and legs but a big midsection, that’s the visceral or apple-shaped obesity, and then there are also people who tend to accumulate more fat in their thighs, their arms and their buttocks, what we would call subcutaneous obesity.
Studies have shown that if you take equally obese individuals, those with a visceral pattern of obesity are more likely to have diabetes, to have heart disease, to have certain kinds of cancer, even to have increased mortality.
And this could be because beige fat arises mainly in subcutaneous tissue?
Yes. One of the distinctions between subcutaneous and visceral fat cells is that subcutaneous fat is more likely to contain thermogenic beige adipocytes, whereas visceral fat lacks beige adipocytes and has more of an inflammatory character.
That distinction is very clearly true in mouse models. How true it is in humans is less clear because everything in humans is more variable depending on genetics and diet and other lifestyle factors.
Ana Gerschenfeld works as a Science Writer at the Science Communication Office at the Champalimaud Neuroscience Programme
Edited by: Catarina Ramos (Science Communication Office).
Photo: The Rockefeller University.
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