Repeated attempts to activate brown fat with drugs have failed – despite its association with a lower risk of type 2 diabetes, obesity and cardiovascular disease. New research now shows that Greenlanders activate brown fat far more easily than Danes in cold conditions. The finding may bring researchers closer to understanding the mechanisms that determine whether brown fat can be exploited therapeutically.
Brown fat has become a central focus of research because it acts as the body’s own heater: when activated, it burns energy to produce heat. Increasingly, researchers consider it not simply as a tissue a person has more or less of but as a biological function that can be switched on – and, in doing so, influence some of the most widespread lifestyle-related diseases in high-income countries, including type 2 diabetes, obesity and cardiovascular disease.
Heat production can be triggered by cold, among other things, and a new study now shows that Greenlanders are far better than Danes at this particular activation – a difference that may point to biological mechanisms researchers have so far been unable to access, not least because they are rarely this clear-cut in adults.
According to researchers behind the study, this contrast is especially interesting because it opens the possibility of identifying the mechanisms that govern the activation of brown fat and that previous research has largely been unable to isolate.
“If we can activate these mechanisms with drugs, we may be able to reduce the risk of type 2 diabetes, obesity and cardiovascular disease. Pharmaceutical companies have tried for many years to exploit brown fat but so far without success, largely because of side-effects. With our study, we now have a first opportunity to understand what it takes to activate brown fat in other ways,” says physician and PhD Mette Motzfeldt Jensen from Queen Ingrid’s Hospital in Nuuk, Greenland.
The research, which was conducted at Aalborg University, Aalborg University Hospital and Ilisimatusarfik (the University of Greenland), has been published in the Journal of Clinical Endocrinology & Metabolism.
Brown fat activation shaped by genetics and cold
Before the study, the researchers hypothesised that Greenlanders both have more brown fat and are better at activating it. One plausible explanation is that repeated exposure to cold throughout life may train the body’s ability to use brown fat – even in adulthood.
It is therefore reasonable to assume that both environment and genetics favour greater brown fat activity among Greenlanders than among Danes, whose fat metabolism also differs – in part due to Greenlanders’ traditional diet rich in fat from marine mammals.
To test this hypothesis, the researchers carried out an experiment in which they exposed 10 Greenlanders and 10 Danes to cold. Participants were invited to experimental sessions in which they lay under a cooling blanket, while the activation of brown fat was measured independently using imaging techniques.
The study included 20 participants. That number is sufficient to demonstrate clear physiological differences but not to determine how widespread the underlying mechanisms may be in the wider population.
The participants were cooled until they felt cold but without starting to shiver, since shivering would interfere with the measurements.
The researchers then scanned the participants using positron emission tomography/computed tomography imaging, which can measure the activation of brown fat by using radioactive glucose markers – a tracer that accumulates in areas of the body where cells are using extra energy, directly measuring tissue energy consumption during cold exposure.
On a separate day, the researchers carried out the same measurements without cold exposure, to directly compare the activation of brown fat during cooling with each participant’s baseline level.
Cold triggers a far stronger brown-fat response in Greenlanders
Cold exposure increased brown fat activation by around 45-fold for Danes and by as much as 170-fold for Greenlanders compared with their own baseline measurements. In both groups, activation rose from a very low starting point to a clearly active level. This result suggests that the ability to activate brown fat in adulthood is not necessarily lost but can vary markedly between individuals.
When the two groups were compared directly, Greenlanders activated around six times as much brown fat as Danes. This was the case even though both groups experienced the same drop in core body temperature during the experiment – a finding that indicates a genuine difference in tissue response rather than differences in the degree of cold exposure itself.
“This tells us that Greenlanders activate brown fat to a greater extent when exposed to cold. It is still unclear whether this difference is driven by genetics or by lifelong environmental adaptation – partly because the study cannot distinguish between heredity and early exposure to cold,” says Mette Motzfeldt Jensen.
But it is precisely this uncertainty that gives the findings direction. The results point to biological mechanisms that can, in principle, be influenced – even if the study itself cannot determine whether the differences arise from genetics, environment or the interaction between the two.
The hunt for the molecular signals behind the activation of brown fat
The experiment also showed that core body temperature fell by 0.5°C for both Greenlanders and Danes. The groups did not differ in their ability to retain heat or generate new heat overall – indicating that the observed differences in brown fat activation cannot be explained by differences in the degree of cold exposure.
Greenlanders did, however, maintain a higher skin temperature throughout the experiment. According to Mette Motzfeldt Jensen, this is likely due to mechanisms other than the activation of brown fat itself.
During the experiment, the researchers took blood samples from participants every 15 minutes. These samples are now being analysed to identify circulating signalling molecules – small substances in the blood that may be involved in triggering brown fat activation – enabling the imaging results to be linked to possible underlying molecular mechanisms.
The blood analysis is being carried out by Torben Hansen and his group at the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen in Denmark.
If the researchers are able to identify the molecular signalling pathways that activate brown fat, the effect may eventually be mimicked pharmacologically. In the longer term, this could shift brown fat from being a biological peculiarity of some individuals to a function that can, in principle, be activated among many people.
“Precisely because Greenlanders activate brown fat so effectively, they are an obvious group to study. And if we can measure brown fat activation in the blood rather than relying on expensive scanners, it will also make future studies far easier to carry out,” concludes Mette Motzfeldt Jensen.
