Chemical messenger orexin poised to spearhead obesity research rejuvenation

07 Aug 2024 --- Dopamine and serotonin, discovered in the early and mid-20th century, were fiercely studied for their effects on the body’s reward system. However, Swiss researchers from the Eidgenössische Technische Hochschule (ETH) Zürich discovered that the brain’s chemical messenger orexin and orexin neurons mediate decisions to snack or exercise.

The scientists posit that the findings are transferable to humans and will spearhead a new era of obesity research and strategies to promote physical activity. 

The roles of the serotonin and dopamine chemical messengers have now largely been decoded. Orexin was discovered 25 years ago and researchers are only now beginning to clarify its functions step by step. We catch up with the study’s lead author, Denis Burdakov, professor of Neuroscience at ETH Zürich, who has devoted his efforts to studying orexin.

“The orexin system branches from a cluster of neurons in the hypothalamus, which is the brain’s only source of the peptide orexin. Blocking this system has broad effects but generally results in decreased energy expenditure and motivation,” Burdakov, tells Nutrition Insight. 

“The effects of blocking orexin are usually only studied in one physiological modality at a time. Only a fraction of studies, including ours, have begun examining how blocking the orexin system may influence interactions between multiple physiological modalities such as exercise and snacking.”

Juggling the milkshake and the grind
The researchers claim that the neuroscientific fundamentals gleaned through the research experiments are relevant because many people are not exercising enough. The additional tendency to frequently skip over exercise in favor of snacking has been attributed to a blocked orexin system. 

“Understanding how the brain prioritizes eating over exercise would be beneficial to efforts combating obesity and cardiovascular diseases. But note that the opposite is dangerous as well: prioritizing exercise over eating too much could lead to conditions such as activity-based anorexia,” Burdakov explains.

“The brain must carefully balance choices to eat or exercise, as maladaptive decisions can lead to a variety of devastating disorders.”

The current research findings in mice were published in Nature Neuroscience. It pinpoints what happens in the brain when it mediates between snacking and exercising. The researchers devised a sophisticated behavioral experiment for mice, in which they could choose freely from eight different options in ten-minute trials.

These included a wheel they could run on and a “milkshake bar” where they could enjoy a standard strawberry-flavored milkshake. “Mice like a milkshake for the same reason people do. It contains lots of sugar and fat and tastes good,” says Burdakov.

The scientists compared mice with a normal functioning orexin system and one with a blocked system, either because of a drug or genetic modification of their cells. The creatures with a blocked orexin system opted more frequently for milkshakes and less for exercise.

“The orexin system, like dopamine, interacts with all parts of the brain. This includes interactions with other proposed neural drivers of voluntary exercise, such as endocannabinoid systems and drivers of snacking, such as other hunger neurons in the hypothalamus,” Burdakov explains.

“Furthermore, it should be noted that orexin has direct interactions with the dopamine system. Future studies will need to selectively block or enhance the influence of orexin on systems such as these. I expect we will see a lot more circuit-based decoding of orexin’s influence on a wide range of behaviors — including exercise and snacking — very soon.”

In their experiments with mice, the researchers showed that orexin plays a pivotal role among more than a hundred messenger substances active in the brain. 

“In neuroscience, dopamine is a popular explanation for why we choose to do some things but avoid others,” says Burdakov. This brain messenger is critical for our general motivation. 

“However, our current knowledge about dopamine does not easily explain why we decide to exercise instead of eating. Our brain releases dopamine both when we eat and when we exercise, which does not explain why we choose one over the other.” 

Testing two orexin systemsSwiss researchers posit orexin as the most exciting chemical messenger of the era to inspire future research about the body’s reward system.
The mice with an intact orexin system spent twice as much time on the running wheel and half as much time at the milkshake bar as those with blocked orexin systems. However, the behavior of the two groups didn’t differ in experiments where the mice were offered either the running wheel or the milkshake. 

“This means that the primary role of the orexin system is not to control how much the mice move or how much they eat. Rather, it seems central to making the decision between one and the other when both options are available,” Burdakov says. Without orexin, the decision was strongly in favor of the milkshake, and the mice gave up exercising in favor of eating. 

The researchers hypothesize that orexin may also be responsible for this decision in humans. The brain functions involved are practically the same in both species. Isolating the roles of orexin’s interactions with other brain areas could broaden understanding of the target region and suggest a genetically defined entry point for therapeutic modulation of these systems and their associated behaviors.

“It will now be a matter of verifying our results in humans. This could involve examining patients who have a restricted orexin system for genetic reasons — this is the case in around one in two thousand people,” says Daria Peleg-Raibstein, group leader at ETH Zurich and co-lead of the study. 

“These people suffer from narcolepsy (a sleeping disorder). Another possibility would be to observe people who receive a drug that blocks orexin. Such drugs are authorized for patients with insomnia.”

“If we understand how the brain arbitrates between food consumption and physical activity, we can develop more effective strategies for addressing the global obesity epidemic and related metabolic disorders,” says Peleg-Raibstein. “In particular, interventions could be developed to help overcome exercise barriers in healthy individuals and those whose physical activity is limited.”

However, Burdakov points out that these would be important questions for scientists involved in human clinical research. His research team is dedicated to basic neuroscientific research. Next, Burdakov wants to find out how the orexin neurons interact with the rest of the brain when making decisions.

“Because the orexin system is also present in humans, it is tempting to speculate that our findings may also apply to humans as well. Therefore, activating the orexin system using an agonist could help us maintain exercise decisions, even when the snack bar is nearby,” Burdakov explains.

“However, to the best of my knowledge, I don’t believe any orexin receptor agonists have been used in a clinical setting. There are, however, exciting new small-molecule candidates. To begin any clinical trial in humans, we will first need to wait for guaranteed efficacy and safety of newly developed drugs targeting the orexin system.”

By Inga de Jong