Researchers may have found the key to burning more calories

Breaking new ground 11. jul 2021 3 min PhD Olivia Sveidahl Johansen Written by Kristian Sjøgren

Research in Denmark shows that a specific receptor on the surface of brown fat is a relevant target for the future treatment of people with obesity.

Metabolism researchers have been interested in brown fat for many years, since it seems to hold the key to activating calorie-burning and counteracting obesity. Even though there have been various hints suggesting considerable potential of brown fat, this potential has remained untapped.

However, researchers in the laboratory of Zachary Gerhart-Hines, a Novo Nordisk Foundation Distinguished Innovator, have made a breakthrough discovery surrounding a promising receptor on the surface of brown fat cells, called GPR3, that might open new therapeutic avenues for people with metabolic disease.

The calorie-burning capacity of brown fat rises substantially when cells within the tissue are made to produce higher levels of GPR3 receptors. In fact, experiments show that mice are unable to gain weight when their GPR3 levels in brown fat are significantly boosted. The researchers even developed a prototype of a therapeutic strategy that caused mice to burn more calories for a whole month after one injection.

“Our findings indicate that increasing the levels of GPR3 receptors could enhance the body’s calorie-burning potential so that people either lose weight or maintain the weight already lost. This presents opportunities in treating not only individuals living with obesity but also people with a wide array of other metabolic diseases,” explains first author Olivia Sveidahl Johansen, a PhD Fellow at the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen and ADIPOSIGN - Center for Adipocyte Signaling.

The research has been published in Cell.

Brown fat is a hot topic

Brown fat has gotten a lot more attention in metabolic research since 2009, when its presence in adult humans was confirmed.

Unlike white fat, which stores energy, brown fat holds the capacity to increase energy expenditure.

Brown fat is activated by cold when the fat tissue burns glucose and fat from the blood in order to create heat.

“The reason why we are so interested in brown fat is that we think it may hold the key to counteracting obesity and diabetes by increasing basal metabolism and draining excess glucose and fat from the blood. We would therefore like to find safe methods to activate brown fat,” says Olivia Sveidahl Johansen.

Surface receptors can activate brown fat and burn calories

An obvious approach to activating brown fat is to use the surface receptors that activate the fat cells when people are exposed to cold. However, the receptors currently known to activate brown fat may not be pharmaceutically attractive because they are the fight-or-flight receptors activated by norepinephrine.

The problem with norepinephrine-activated receptors is that norepinephrine analogues activate not only brown fat but also other types of cells throughout the body, resulting in increased blood pressure and heart rate.

“We therefore want to find means to activate brown fat independently of the traditional receptors. Ideally, we will activate brown fat using receptors that avoid triggering the adverse responses in other tissues, such as the heart,” explains Olivia Sveidahl Johansen.

Receptors play a key role in activating brown fat

In the study, the researchers exposed mice to cold and found that the number of GPR3 receptors on the surface of the brown fat cells increased dramatically.

The production of GPR3 receptors in brown fat cells reached a maximal level after 8 hours of cold exposure, while the brown fat activity was through the roof.

“This is interesting because GPR3 is similar to the norepinephrine receptors in its effects on brown fat activity but is controlled by something else. Further, the GPR3 receptors are not upregulated in other tissues but only in the brown fat. In addition, our studies show that GPR3 does not need to be activated by external signalling molecules like other receptors but instead displays constant activity. Therefore, the more receptors there are, the greater the brown fat activity,” says Olivia Sveidahl Johansen.

Having more GPR3 receptors suppresses obesity

To explore the therapeutic potential of GPR3 receptors, the researchers genetically engineered mice with high levels of GPR3 receptors in their brown fat cells.

They found that these mice were resistant to obesity and were unable to gain weight despite being fed a diet very rich in calories.

The researchers also induced overexpression of GPR3 receptors in obese mice. Here they found that the body weights of the animals declined substantially while uptake of glucose and fat into brown fat tissue improved.

“This indicates that GPR3 can enhance natural calorie-burning. Ultimately, we will seek therapeutic strategies to increase the presence of this receptor on the surface of brown fat cells, because this may reduce people’s weight,” explains Olivia Sveidahl Johansen.

Increased calorie-burning in mice injected with experimental treatment

Olivia Sveidahl Johansen and her colleagues have already tested the potential of such a drug candidate and used a virus to increase the levels of GPR3 in the brown fat cells.

They tested this experimental drug on mice, and one dose was enough to increase the calorie-burning of the mice for an entire month.

Olivia Sveidahl Johansen has difficulty hiding her enthusiasm.

“We have shown that GPR3 plays an important role in regulating calorie-burning, and we have shown that the levels of GPR3 have the potential to be regulated using clinically viable approaches. This opens up opportunities for curing many metabolic diseases by activating brown fat using a completely new form of therapy. In addition, the study provides new knowledge about brown fat biology,” concludes Olivia Sveidahl Johansen.

Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis” has been published in Cell. Several authors are employed at the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.

Olivia Sveidahl Johansen is also affiliated with ADIPOSIGN - Center for Adipocyte Signaling. The centre has received a grant from the Novo Nordisk Foundation.

The overarching theme of the group is to uncover how environmental cues govern adipose biology and coordinate organismal energy metabolism. Specifical...

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