Brown fat, or thermogenic adipose tissue, appears to act as a "nutrient sink," consuming glucose and lactate, among other metabolites, say US researchers in a mouse study that supports its potential role in tackling obesity and even cancer.
David A. Guertin, PhD
The research, published recently in Nature Metabolism, was led by David A. Guertin, PhD, Program in Molecular Medicine, UMass Chan Medical School, Worcester, Massachusetts.
To find out more about the study, its clinical implications, and whether the results are translatable to humans, Medscape Medical News caught up with Guertin, asking him to explain some of the concepts behind the research.
What is adaptive thermogenesis, and why is it important in temperature regulation?
Adaptive thermogenesis is a physiologic process that occurs in a special type of fat cell, called a brown adipocyte, in which intracellular stored lipids and nutrients taken up from the blood are catabolized to generate heat.
The heat generated by these thermogenic adipocytes is critical for warming the blood and maintaining body temperature in cold environments, and is especially critical in human infants and small mammals, which are more sensitive to low temperatures.
The process is stimulated by the sympathetic nervous system, especially in response to feeling cold, but it can be activated by other stresses as well.
While adaptative thermogenesis is also called nonshivering thermogenesis to distinguish it from muscle shivering, both means of generating heat can work together to maintain body temperature.
Why is it considered a potential target for obesity?
Adult humans have brown adipocytes in specific locations in the body called brown adipose tissues (BAT) or, more simply, "brown fat."
Intriguingly, clinical data show that the more BAT you have, the more likely you are to be protected against cardiometabolic disorders associated with obesity.
Since obesity results from an imbalance between energy intake and energy expenditure, one model proposes that brown adipocytes rebalance this formula by expending the excess energy (calories) as heat rather than storing it.
This has been referred to as the "nutrient sink" model, and the ability to activate this process therapeutically is a very attractive antiobesity strategy.
Why was it important to understand which circulating metabolites BAT uses for thermogenesis?
It is still not clear why brown fat is so beneficial for human health, and thus there is strong rationale for understanding its metabolism and how it cooperates with other tissues in the body.
For example, prior to our work, the field lacked a broad quantitative picture of how much any individual nutrient from the blood was used by brown fat, or which specific nutrients brown fat prefers to use to make heat — such as lipids, glucose, amino acids, etc. Knowing this information helps us identify more precise strategies to activate brown fat.
In addition, circulating metabolites sometimes also have messenger functions, similar to those of hormones, that stimulate physiologic processes such as adaptative thermogenesis. Highly metabolic tissues also put metabolites back into the blood, which can send messages to the brain and other tissues.
We don't have a lot of information yet on how brown fat might engage in these processes, and so our study also aimed at finding these special metabolite messengers.
You found that glucose and lactate predominate as BAT fuel sources. What does that tell us?
The major fuels used by brown fat have been debated for a long time.
Our study suggests that BAT in mice mainly prefers glucose, and lactate, which is generated from glucose. On one hand, this shows us that thermogenic adipocytes may be especially useful in treating hyperglycemia, or even tumors, by reducing the amount of circulating glucose.
It also tells us that we need to focus more on why brown fat needs so much glucose. Other studies suggest that glucose is not just used as a fuel to generate heat but also may have other important functions in keeping brown adipocytes active and healthy.
We need to know that information so that therapeutic strategies targeting brown adipocytes can be optimized to have the best chance of success.
It's worth noting that we did our study in mice which had free access to food. If the mice were fasting, they would use more lipids from the blood to supplement for the lack of available glucose, but we think that a baseline amount of glucose is still necessary.
What could be the clinical implications of your results if replicated in humans?
They suggest that glucose is an important resource that thermogenic adipocytes cannot do without, and moreover, that glucose is more than just a carbon source.
Resolving those other functions of glucose may provide insight into mechanisms to stimulate these cells or help explain why overweight or obese people who are insulin resistant have less brown fat activity, as insulin stimulates glucose uptake.
Beyond glucose, if any of these other metabolites made or released by brown fat have beneficial messenger functions, there may be ways to pharmacologically mimic them.
How easily do you think your findings could be applied to humans?
On a fundamental level, the basic cellular mechanisms that drive adaptative thermogenesis are likely the same between mice and humans, but the wiring to the sympathetic nervous system is a bit different.
This is why it's important to look deeply at brown fat metabolism in mouse models to find pathways fundamental to the basic mechanisms of adaptative thermogenesis in both mice and humans, which could reveal unique therapeutic opportunities.
Another big challenge with comparing humans and mice is that humans typically keep their environment warm, so their brown fat is not that active.
In contrast, mice are often raised their entire lives in a facility kept at room temperature, around 22 °C (72 °F). While comfortable for the humans working with them, it's cold for a small mouse, and so mice live with constantly active brown fat.
We can change the mouse environment to alter mouse brown fat activity, but that can't be done with people. This makes comparative studies difficult.
Nevertheless, studies have shown that people who live in cold climates often have more brown fat, and, conversely, mice raised in warmer environments have brown fat that looks a lot more like human brown fat.
What further research do you have planned, or are looking forward to, in this area?
This is the most fun part of what we do, and I've been fortunate to have an amazing team passionately working on these questions.
One is to figure out why glucose is so important for these fascinating cells, which will keep us busy for years. We also need to modify the dietary conditions to determine whether the body prioritizes the use of glucose for adaptive thermogenesis even when there isn't much available.
Another goal is to test whether any of the other metabolites we identified have bioactive functions. We also discovered a unique role for glutamine metabolism in brown fat, through the consumption of amino acids, that we haven't yet resolved.
Finally, we want to understand how and why brown fat protects other organs from metabolic diseases, and we are just at the tip of the iceberg here.
The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute on Alcohol Abuse and Alcoholism; the National Heart, Lung, & Blood Institute; the National Institutes of Health; the AASLD Foundation Pinnacle Research Award in Liver Disease; the Edward Mallinckrodt, Jr. Foundation Award; and the Basic Science Research Program of the Ministry of Education (South Korea).
No relevant financial relationships were disclosed.
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