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 that 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.