Brown fat may hold key to treatment of cardiometabolic disorders

Aaron M. Cypess

Not all fat is bad. In fact, some fat can be very good — even body fat, according to Aaron M. Cypess, MD, PhD, MMSc, acting chief of the translational physiology section of the diabetes, endocrinology and obesity branch of the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH. Evidence from the past decade has pointed toward benefit from brown fat, and researchers are exploring its potential for treating obesity, diabetes and other cardiometabolic disorders.

In a discussion with Healio, Cypess outlined the role of brown fat in the human body, how our understanding of the organ has developed, how it may be utilized in obesity treatment and what we still need to learn.

What is the difference between brown and white fat?

Cypess: Functionally, the role of white fat is to store calories, which then get used by the body when we haven’t eaten. The role of brown fat is to hold onto calories temporarily, particularly those from fat, and then to burn them up as heat when there is a sensation of cold.

At the endocrine level, there are many differences between the tissues, mostly not known in terms of what hormones are released by the two different kinds of fat. White fat, we know, releases leptin, which helps regulate appetite and even influences the menstrual cycle. White fat also releases hormones that affect systemic inflammation and energy homeostasis. Very little is known right now about what hormones brown fat releases in humans. There are preliminary findings to suggest that it does secrete hormones to help muscle and brown fat itself take up fat and glucose to then support the generation of heat.

Weight loss scale and tape measure 2019 
Evidence from the past decade has pointed toward benefit from brown fat, and researchers are exploring its potential for treating obesity, diabetes and other cardiometabolic disorders.
Source: Adobe Stock

How much brown fat does the average human have and what factors influence changes in that amount?

Cypess: Based on the studies that we and our colleagues have done, where there is controlled activation of brown fat either with mild cold exposure or the medication mirabegron (Myrbetriq, Astellas Pharma), we find that an average woman or man in the range of 18 to 40 years old has between 50 g and 100 g of brown fat. We have seen more than 500 g — which equals more than a pound — in the people with the most brown fat. In addition, population studies show that people who are obese and people who are older have less brown fat. It would be fascinating to see over time whether the amount of brown fat changes as people get older or gain or lose weight.

What does brown fat do and how does it work?

Cypess: What happens is that brown fat has the ability to short circuit the electron transport chain. The electron transport chain is in every mitochondrion in the cell and is the place where food calories are turned into the chemical energy necessary for life, a molecule called ATP. Brown fat uses a special protein to short circuit the process so that instead of turning fats and carbohydrates into ATP, it turns them into heat. The analogy I like to give is that if you’re in your car, and you shift the car into neutral, and then you press the gas pedal, you’re going to use up a lot of fuel, but the car doesn’t move — all that gasoline is turned into heat.

Why is it good to have more brown fat?

Cypess: We know from preclinical models that more brown fat is associated with better health, including improved glucose metabolism, insulin action, cholesterol profile and resistance to weight gain. Now in humans, we are beginning to see these results in the clinical trials. We already know that more brown fat is associated with people being lean, though the cause and effect have not yet been firmly established. In the initial studies where people have been treated with cold exposure or mirabegron to increase their brown fat, there have also been improvements in insulin sensitivity and cholesterol profile. So, it may be that having more brown fat in humans could be beneficial.

How might brown fat be targeted to treat conditions such as diabetes and obesity?

Cypess: I like to think of activating brown fat as being similar to exercise. With exercise, the muscles that are moving have to consume a lot of calories to maintain them. In a similar way, brown fat has to be supported with lots of fuel to be able to generate heat. When these things occur, such as exercise or brown fat activation, you see a series of coordinated responses by the body. For example, when brown fat is activated, it consumes fat and glucose from the blood, so over time activated brown fat ends up taking fat from other places and consumes it. That’s a good thing because it can reduce the fat burden in tissues such as the liver and the white fat, which may help reduce inflammation and the risks for atherosclerosis and certain kinds of heart disease.

Also, there’s evidence from preclinical models established by teams led by our colleagues Joerg Heeren, PhD, of the department of biochemistry and molecular cell biology at the University Medical Center Hamburg – Eppendorf, and Patrick Rensen, PhD, professor of endocrinology at Leiden University Medical Center, that when brown fat is activated, it takes up a lot of fatty acid and cholesterol. That cholesterol then gets turned ultimately into helpful bile acids and the HDL “good” cholesterol. Bile acids are of particular interest because they are involved in affecting the formation of gallstones, whole-body inflammation and the types of bacteria in the gut, known as the microbiome. The study we just published shows that the same processes may be happening in humans as well, with increases in bile acids and HDL cholesterol.

Based on our work and the evidence provided by our colleagues, it could be that in the future, human brown fat could be activated by mild cold or a drug like mirabegron to improve the cholesterol profile and insulin sensitivity in people with diseases like type 2 diabetes and heart disease.

How has our understanding of brown fat, specifically the benefits of having more brown fat, changed in the last decade?

Cypess: With humans, the big discoveries from 10 years ago were that there is functional brown fat in humans. While that may seem trivial today, as recently as 12 to 13 years ago, many of the top people in the field said there was no brown fat at all in adult humans. The scientists studying metabolism have therefore been spending the past decade trying to determine what it means for there to be a new organ in the body.

The main advances have been in two areas: technical and functional. Technically, the field has gotten much better at using sophisticated imaging such as PET/CT and MRI to define where human brown fat is and how to track its activity over time. In terms of function, the advances have come in understanding what kinds of nutrient fuels brown fat uses, such as the kinds of fats, carbohydrates and proteins it consumes during fasting and feeding, and how much energy brown fat is capable of generating.

What research is still needed?

Cypess: Even with a decade of discoveries, there are large voids in terms of understanding human brown fat. We need to get much better at precisely measuring how much there is and how many calories it consumes so we can see what role it can play in weight loss. We need to understand how to make more, from the detailed molecular signals that regulate the process to the safest drugs that increase the amount of brown fat in the body. Most importantly, we need to determine how this newly discovered functional organ communicates with the rest of the body. Brown fat may be the central hub that regulates the body’s response to cold exposure, telling the white fat, skeletal muscle and brain what to do. It could be involved in other processes as well, still waiting to be discovered.

The kind of research needed is a series of elegant experiments done in the lab, where precise molecular mechanisms can be highlighted, and these are then translated into clinical trials in humans, where it can be determined how brown fat activity can be used to improve human health.

Reference:

O’Mara AE, et al. J Clin Invest. 2020;doi:10.1172/JCI131126.

For more information:

Aaron M. Cypess, MD, PhD, MMSc, can be reached at aaron.cypess@nih.gov.

Disclosure: Cypess reports no relevant financial disclosures.

Aaron M. Cypess

Not all fat is bad. In fact, some fat can be very good — even body fat, according to Aaron M. Cypess, MD, PhD, MMSc, acting chief of the translational physiology section of the diabetes, endocrinology and obesity branch of the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH. Evidence from the past decade has pointed toward benefit from brown fat, and researchers are exploring its potential for treating obesity, diabetes and other cardiometabolic disorders.

In a discussion with Healio, Cypess outlined the role of brown fat in the human body, how our understanding of the organ has developed, how it may be utilized in obesity treatment and what we still need to learn.

What is the difference between brown and white fat?

Cypess: Functionally, the role of white fat is to store calories, which then get used by the body when we haven’t eaten. The role of brown fat is to hold onto calories temporarily, particularly those from fat, and then to burn them up as heat when there is a sensation of cold.

At the endocrine level, there are many differences between the tissues, mostly not known in terms of what hormones are released by the two different kinds of fat. White fat, we know, releases leptin, which helps regulate appetite and even influences the menstrual cycle. White fat also releases hormones that affect systemic inflammation and energy homeostasis. Very little is known right now about what hormones brown fat releases in humans. There are preliminary findings to suggest that it does secrete hormones to help muscle and brown fat itself take up fat and glucose to then support the generation of heat.

Weight loss scale and tape measure 2019 
Evidence from the past decade has pointed toward benefit from brown fat, and researchers are exploring its potential for treating obesity, diabetes and other cardiometabolic disorders.
Source: Adobe Stock

How much brown fat does the average human have and what factors influence changes in that amount?

Cypess: Based on the studies that we and our colleagues have done, where there is controlled activation of brown fat either with mild cold exposure or the medication mirabegron (Myrbetriq, Astellas Pharma), we find that an average woman or man in the range of 18 to 40 years old has between 50 g and 100 g of brown fat. We have seen more than 500 g — which equals more than a pound — in the people with the most brown fat. In addition, population studies show that people who are obese and people who are older have less brown fat. It would be fascinating to see over time whether the amount of brown fat changes as people get older or gain or lose weight.

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What does brown fat do and how does it work?

Cypess: What happens is that brown fat has the ability to short circuit the electron transport chain. The electron transport chain is in every mitochondrion in the cell and is the place where food calories are turned into the chemical energy necessary for life, a molecule called ATP. Brown fat uses a special protein to short circuit the process so that instead of turning fats and carbohydrates into ATP, it turns them into heat. The analogy I like to give is that if you’re in your car, and you shift the car into neutral, and then you press the gas pedal, you’re going to use up a lot of fuel, but the car doesn’t move — all that gasoline is turned into heat.

Why is it good to have more brown fat?

Cypess: We know from preclinical models that more brown fat is associated with better health, including improved glucose metabolism, insulin action, cholesterol profile and resistance to weight gain. Now in humans, we are beginning to see these results in the clinical trials. We already know that more brown fat is associated with people being lean, though the cause and effect have not yet been firmly established. In the initial studies where people have been treated with cold exposure or mirabegron to increase their brown fat, there have also been improvements in insulin sensitivity and cholesterol profile. So, it may be that having more brown fat in humans could be beneficial.

How might brown fat be targeted to treat conditions such as diabetes and obesity?

Cypess: I like to think of activating brown fat as being similar to exercise. With exercise, the muscles that are moving have to consume a lot of calories to maintain them. In a similar way, brown fat has to be supported with lots of fuel to be able to generate heat. When these things occur, such as exercise or brown fat activation, you see a series of coordinated responses by the body. For example, when brown fat is activated, it consumes fat and glucose from the blood, so over time activated brown fat ends up taking fat from other places and consumes it. That’s a good thing because it can reduce the fat burden in tissues such as the liver and the white fat, which may help reduce inflammation and the risks for atherosclerosis and certain kinds of heart disease.

PAGE BREAK

Also, there’s evidence from preclinical models established by teams led by our colleagues Joerg Heeren, PhD, of the department of biochemistry and molecular cell biology at the University Medical Center Hamburg – Eppendorf, and Patrick Rensen, PhD, professor of endocrinology at Leiden University Medical Center, that when brown fat is activated, it takes up a lot of fatty acid and cholesterol. That cholesterol then gets turned ultimately into helpful bile acids and the HDL “good” cholesterol. Bile acids are of particular interest because they are involved in affecting the formation of gallstones, whole-body inflammation and the types of bacteria in the gut, known as the microbiome. The study we just published shows that the same processes may be happening in humans as well, with increases in bile acids and HDL cholesterol.

Based on our work and the evidence provided by our colleagues, it could be that in the future, human brown fat could be activated by mild cold or a drug like mirabegron to improve the cholesterol profile and insulin sensitivity in people with diseases like type 2 diabetes and heart disease.

How has our understanding of brown fat, specifically the benefits of having more brown fat, changed in the last decade?

Cypess: With humans, the big discoveries from 10 years ago were that there is functional brown fat in humans. While that may seem trivial today, as recently as 12 to 13 years ago, many of the top people in the field said there was no brown fat at all in adult humans. The scientists studying metabolism have therefore been spending the past decade trying to determine what it means for there to be a new organ in the body.

The main advances have been in two areas: technical and functional. Technically, the field has gotten much better at using sophisticated imaging such as PET/CT and MRI to define where human brown fat is and how to track its activity over time. In terms of function, the advances have come in understanding what kinds of nutrient fuels brown fat uses, such as the kinds of fats, carbohydrates and proteins it consumes during fasting and feeding, and how much energy brown fat is capable of generating.

What research is still needed?

Cypess: Even with a decade of discoveries, there are large voids in terms of understanding human brown fat. We need to get much better at precisely measuring how much there is and how many calories it consumes so we can see what role it can play in weight loss. We need to understand how to make more, from the detailed molecular signals that regulate the process to the safest drugs that increase the amount of brown fat in the body. Most importantly, we need to determine how this newly discovered functional organ communicates with the rest of the body. Brown fat may be the central hub that regulates the body’s response to cold exposure, telling the white fat, skeletal muscle and brain what to do. It could be involved in other processes as well, still waiting to be discovered.

The kind of research needed is a series of elegant experiments done in the lab, where precise molecular mechanisms can be highlighted, and these are then translated into clinical trials in humans, where it can be determined how brown fat activity can be used to improve human health.

Reference:

O’Mara AE, et al. J Clin Invest. 2020;doi:10.1172/JCI131126.

For more information:

Aaron M. Cypess, MD, PhD, MMSc, can be reached at aaron.cypess@nih.gov.

Disclosure: Cypess reports no relevant financial disclosures.