Brown adipose tissue may have a role in weight control, body fuel utilization and thermogenesis.
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Endocrinologists have recently been presented with an opportunity to study an organ that was just discovered to be functional in humans, one that can aid in weight loss and weight control and in keeping the body warm, according to experts.
Brown fat is an adipose-like tissue that stores fat and acts like a furnace, eventually burning up calories and generating heat when the body is cold and, at times, when weight loss is needed. During the past decade or so, much basic research on brown fat has centered on its metabolic significance and its activation by cold and insulin, its benefit in energy expenditures, and weight control and loss mechanisms. Its significance in humans is now what is in the front line.
Daniel L. Smith Jr., PhD, said based on previous research in animals, brown fat could be important in metabolism and weight control under certain conditions.
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Steve W. Wood, for UAB
According to Aaron M. Cypess, MD, PhD, assistant professor of medicine at Joslin Diabetes Center and Harvard Medical School, brown fat is “literally one of the most powerful organs in the body, generating more calories per gram of tissue than any other. Since it consumes both glucose and fatty acids, it is possible that we could utilize brown fat to treat obesity and metabolic dysfunction seen in diabetes and hyperlipidemia,” he told Endocrine Today.
Although much has been unveiled about brown fat’s role in humans during the past few years, there are still many unknowns when it comes to physiology and metabolism.
“Previous research in animal models suggests brown fat could be an important factor in metabolism and weight control under certain conditions,” said Daniel L. Smith Jr., PhD, faculty instructor in the department of nutrition sciences at the University of Alabama at Birmingham. “To what extent brown fat participates in similar roles in humans requires further study, but preliminary reports suggest associations of brown fat function with lower body weight and better glucose control (insulin response).”
Endocrine Today spoke with several experts in the field to delve into the potential functionality of brown fat in humans, and the future of this organ and its implications in weight loss and thermogenesis.
Uncovering BAT’s functionality
Mammals possess roughly two types of fat cells: the more well-known white adipocytes, and brown adipocytes. The prominent function of white fat cells is energy storage, whereas brown adipose tissue’s main function is heat production.
W.D. van Marken Lichtenbelt
“Contrasting the white to yellow appearance of white adipose tissue, brown adipose tissue (BAT) is characterized by a light pink to dark red tone, which is caused by the high vascularization and the more granular appearance of the cytoplasm. The latter is caused by the small fat-filled vacuoles and the large amount of mitochondria in the cell,” said W.D. van Marken Lichtenbelt, PhD, associate professor in the department of human biology at the School for Nutrition and Toxicology and Metabolism (NUTRIM), Maastricht University Medical Center, the Netherlands.
Another important trait of BAT is the innervation by the sympathetic nervous system. Given the correct stimulus, brown fat is able to express the unique mitochondrial protein uncoupling protein-1 (UCP1), which, when activated, has the ability to turn food’s chemical energy directly into heat.
“Thus, if we can activate BAT or even can recruit an extra amount of active brown adipose tissue, we can potentially increase our heat production,” van Marken Lichtenbelt said. “That means that the energy expenditure goes up, which will affect our energy balance in a positive way.”
Recent research shows that children and adults have more functional brown fat than experts have previously realized. Almost all people aged 30 years and younger, and about one-third of older people, have brown fat, according to Jan Nedergaard, PhD, professor at the Wenner-Gren Institute at Stockholm University, Sweden.
“This is very encouraging. But as a percentage of body mass, it is about one-tenth of what we see in a mouse. So the question is: Will brown fat be helpful for more than just to keep us warm? Can we use it to do more?” Cypess said.
A study published in Nature led by Bruce M. Spiegelman, PhD, Stanley J. Korsmeyer Professor of Cell Biology and Medicine at the Dana-Farber Cancer Institute and Harvard Medical School, and colleagues showed that, in mice, exercise leads muscle to produce a newly discovered hormone, irisin, which increases brown fat growth along with energy expenditure.
Cypess said the relevance of these findings is twofold: It represents the first hormone identified that is secreted by muscle to cause brown fat to grow, thus showing that brown fat works with other tissues. Second, these results suggest that irisin may be used to increase the body’s brown fat and burn more calories. This could eventually be optimized as a treatment for obesity.
Brown fat could also play an important role in protecting against age-related obesity, according to results of another study, published by Cypess and colleagues in The New England Journal of Medicine. Results demonstrated that the amount of BAT in humans is inversely correlated with BMI.
Another study published recently in The Journal of Clinical Investigation by Denis Richard, PhD, director of the research center at the Quebec Heart and Lung Institute in Canada, and colleagues showed that brown fat is likely the primary organ responsible for generating heat and is metabolically active. They observed, in cold-exposed humans, a significant 1.8-fold increase in the total energy expenditure (excess expenditure of some 250 kcal over 3 hours of cold exposure) due, in significant part, to an increase in the BAT-mediated non-shivering thermogenesis.
“Our findings support a role for BAT in non-shivering thermogenesis in humans,” Richard told Endocrine Today. “We further observed a significant increase in the radio-density of BAT after cold exposure, indicating that the intracellular triglycerides are the main source of energy for thermogenesis, as observed in rodents.”
Until now, studies have only shown glucose uptake, and it has been doubted whether the tissue actually burns food in humans, Nedergaard wrote in an accompanying commentary.
“This was shown to be the case in the article,” he said. “What we are still missing is a good measure of capacity and a solution of how to keep it active.”
Effects on the body
Brown fat interacts with several classical endocrinologic areas either directly or indirectly, according to Nedergaard.
“We have realized within the last 5 years that humans possess an organ we did not earlier recognize, and the function of this may markedly affect the interpretation of other studies, specifically in endocrinology,” he told Endocrine Today. “Metabolic effects of noradrenalin and thyroid hormones are the obvious candidates, but also glucocorticoids and sex hormones may affect brown fat and, in this way, metabolism.”
Many of the good effects of brown fat stem from its specialized function in thermogenesis. This includes its ability to promote lipid utilization and glucose uptake, according to Smith.
Brown fat has been shown to keep the human body warm in a comfortable way, increase energy expenditure, help the body burn off extra calories when too many are consumed and take up glucose (counteracting diabetes) and fat from the blood, which together counteract metabolic syndrome.
Richard said the presence of an active heat-producing effector such as BAT can represent a useful means to dissipate energy and then prevent excess fat deposition.
“Importantly, even though cold exposure can ‘wake BAT up,’ it should not be envisioned as a way to lose weight,” he said.
In general, the negative effects associated with brown fat are still vastly unknown.
Aaron M. Cypess
“It is certainly conceivable that uncontrolled brown fat activity could cause dangerously high body temperatures, but this has not yet been seen,” Cypess said.
Additionally, brown fat activation results from sympathetic nervous stimulation, which has been linked with an increase in heart rate and blood pressure. However, these cardiovascular side effects may occur independent of brown fat, Smith said.
Van Marken Lichtenbelt said animal studies have indicated some tumors may increase BAT activity, and retrospective studies in these patients show increased occurrence of BAT.
“There are indications that brown adipose tissue may be involved, and in these cases, the extra energy consumption is probably not good,” he said.
Potential treatments; road ahead
“Carefully designed, prospective studies assessing brown fat function and particular disease susceptibility remain to be performed,” Smith said. “Whether brown fat can be targeted as a pharmaceutical therapy for weight loss or metabolic-related diseases likewise requires further research.”
To move the field forward, more studies are warranted, including those that focus on how to evaluate brown fat’s mechanisms for how UCP1 works; regulation of growth and regression; how to keep it active; its capacity in humans; brown fat activation by cold and also by pharmacological means; brown fat recruitment; its role in the metabolic syndrome and its effects on the elderly.
Simply put, “we need more knowledge on the biology of BAT,” van Marken Lichtenbelt said. Endocrinologists must also be aware that the major cause of obesity is too much food intake. Although BAT may help, it will not provide benefit if compensated by consuming more.
An additional unanswered long-term question is the potential treatments that can be used to target brown fat, either via environmental temperature controls, certain food components or pharmaceuticals that increase energy expenditure.
“Right now, spending time in the cold certainly works,” Cypess said. “It’s not all that comfortable as a long-term approach, and it’s not clear how effective that would be over time.”
Richard said although studies demonstrating BAT’s presence in humans and its metabolic activity have rejuvenated interest in the study of BAT in energy balance and obesity, more research is needed to investigate the conditions for which this may be applied, such as diets, environments and drugs.
“Our group and others are also involved in deciphering the brain pathways involved in the control of BAT thermogenesis,” he said. “BAT activity is physiologically controlled by the sympathetic nervous system, whose activity is governed by many brain sites, including sites involved in energy balance regulation.”
Studies are also under way to determine how to make the tissue grow, particularly by pharmacological means, so that it can burn calories in a clinically meaningful and safe manner. Additionally, ongoing studies are aimed at investigating the molecular biology of how to transform white adipose tissue into brown.
“Right now, we can say there is great potential for using brown fat as a therapeutic tool as well, but it will take more good experiments to find out just how helpful it will be in treating obesity and diabetes,” Cypess said.
Improved understanding of the regulation and recruitment of BAT may ultimately lead to the development of treatments for obesity and related disorders such as type 2 diabetes, the experts said.
“The realization that we possess a ‘new’ organ must let us rethink earlier ideas on metabolism, and the more we know about this organ, the larger is the chance that we can be helped by its activity,” Nedergaard said. – by Tara Grassia
For more information:
- Boström P. Nature. 2012;481:463-468.
- Cannon B. J Clin Invest. 2012;122:486-489.
- Cypess AM. N Engl J Med. 2009;360:1509-1517.
- Orava J. Cell Metab. 2011;14:272-279.
- Ouellet V. J Clin Invest. 2012;122:545-552.
- Saito M. Diabetes. 2009;58:1526-1531.
- van Marken Lichtenbelt WD. N Engl J Med. 2009;360:1500-1508.
- Vijgen G. PLoS One. 2011;6:e17247.
- Virtanen KA. N Engl J Med. 2009;360:1518-1525.
- Zingaretti MC. FASEB J. 2009;23:3113-3120.
Disclosure: Dr. Cypess has consulted for Bristol-Myers Squibb and Pharmalucence Inc. Dr. Nedergaard is a consultant for several companies investigating the possibility to use brown fat in humans to improve health. Dr. Spiegelman is founder and shareholder in Ember Therapeutics, which has licensed irisin from the Dana-Farber Cancer Institute. Drs. Richard, Smith and van Marken Lichtenbelt report no relevant financial disclosures.
Considering data on diet-induced thermogenesis, do you believe brown fat will be clinically useful?
Our data have been linked to the effect of exercise and activating fat and diet-induced thermogenesis.
Bruce M. Spiegelman
We know that human beings have brown fat and the question is what can activate it how, how much can it activate, and are there any side effects, among many other unknown answers to questions on brown fat. Right now, with the information we have available, we just don’t know the answer to these questions. We do know it can be activated in rodents, and I am optimistic the data will come out as it does. It is certainly a new idea with new data, but how far it goes remains to be seen.
I think brown fat will have clinical utility, although this is based on rodent data. Thus far, the pathways look robust and it is reasonable because most humans have substantial depots of brown fat. There is some emerging correlative data that it correlates with the amount of obesity and diabetes; however, the proof of principle is not done. At this point, my thought is it looks very promising.
Bruce M. Spiegelman, PhD, is the Stanley J. Korsmeyer Professor of Cell Biology and Medicine at the Dana-Farber Cancer Institute, Harvard Medical School.
Disclosure: Dr. Spiegelman is founder and shareholder in Ember Therapeutics, which has licensed irisin from the Dana-Farber Cancer Institute.
Diet-induced thermogenesis is a controversial subject and has been debated for some time.
Preformed brown fat exists primarily as an adaptive mechanism for cold temperatures (ie, generating heat to maintain body temperature, particularly in newborns and some hibernating animals). There is evidence that heat is generated during food consumption, but its origin is not clear, and whether this is from brown-like adipocytes is uncertain. Also, there is a question whether certain diets can stimulate brown-like adipocytes via activation of the sympathetic nervous system at specific fat depots. The evidence is not compelling, but with greater refinement in our imaging and functional studies, it could be addressable. In the meantime, total food intake is a critical determinant of weight gain due to expansion of white adipose storage, and exercise remains a great way to lose weight, although all the mechanisms for that decline are not certain.
It is still unclear what happens to preformed BAT in the interscapular region with aging, although it appears not to be as ‘brown’ with age. We know that brown-like adipocytes can exist in white fat depots across ages and can be stimulated by the sympathetic nervous system. That said, it is possible if you have an agent that is a beta-adrenergic agonist that could turn on brown-like adipocytes, this might have clinical utility. Whether you can chronically turn on the BAT in the interscapular region is unclear. It can be done with cold exposure very transiently, but long term, it has not been determined.
Clifford Rosen, MD, is a senior scientist at Maine Medical Center Research Institute.
Disclosure: Dr. Rosen reports no relevant financial disclosures.