Researchers find the 'switch' that deactivates brown fat

European researchers have found a protein that is responsible for turning off brown fat activity, in a breakthrough which could help to address obesity and related health problems. Their discovery has been described in the journal Nature Metabolism.

Brown fat, also known as brown adipose tissue (BAT), is a type of fat in our bodies that’s different from the white fat around our belly and thighs that we are more familiar with. It helps to burn calories from the foods that we eat into heat, which can be especially helpful when we’re exposed to extremely cold temperatures.

Scientists previously thought that only small animals like mice and newborns had brown fat, but new research shows that a certain number of adults maintain their brown fat throughout their life. Because brown fat is so good at burning calories, scientists are trying to find ways to activate it safely using drugs that boost its heat-producing abilities.

The research groups of Professor Jan-Wilhelm Kornfeld from the University of Southern Denmark and the Center for Adipocyte Signaling (ADIPOSIGN), and Dagmar Wachten from the University Hospital Bonn and the University of Bonn, have now found that brown fat has a previously unknown built-in mechanism that switches it off shortly after being activated, limiting its effectiveness as treatment against obesity. The protein responsible for this switching-off process is known as ‘AC3-AT’.

“Looking ahead, we think that finding ways to block AC3-AT could be a promising strategy for safely activating brown fat and tackling obesity and related health problems,” said first author Hande Topel, a senior postdoc at the University of Southern Denmark and ADIPOSIGN.

The research team found the switch-off protein using advanced technology predicting unknown proteins. Topel explained, “When we investigated mice that genetically didn’t have AC3-AT, we found that they were protected from becoming obese, partly because their bodies were simply better at burning off calories and were able to increase their metabolic rates through activating brown fat.”

Two groups of mice were fed a high-fat diet for 15 weeks, which rendered them obese. The group that had their AC3-AT protein removed gained less weight than the control group and were metabolically healthier.

“The mice that have no AC3-AT protein also accumulated less fat in their body and increased their lean mass when compared to the control mice,” said co-author Ronja Kardinal, a PhD student at the University of Bonn. “As AC3-AT is found not only in mice but also in humans and other species, there are direct therapeutic implications for humans.”

Although the prevalence of brown fat decreases as humans age, and despite adults not having as much brown fat as newborns, it can still be activated, for instance by cold exposure. When it gets activated, it enhances the rate of metabolism of these individuals, which again may help to stabilise weight loss in conditions where calorie intake is (too) high. Intriguingly, this study not only identified AC3-AT — which is a shorter, previously unknown form of the AC3 protein — it also identified other unknown protein/gene versions that respond to cold exposure, similar to AC3-AT.

“However, further research is needed to elucidate the therapeutic impact of these alternative gene products and their regulatory mechanisms during BAT activation,” Wachten said.

Kornfeld concluded, “Understanding these kinds of molecular mechanisms not only sheds light on the regulation of brown fat but also holds promise for unravelling similar mechanisms in other cellular pathways. This knowledge can be instrumental in advancing our understanding of various diseases and in the development of novel treatments.”

Image ©University of Southern Denmark.