Mighty Mouse: Could a Part of the Brain Unlock the Key to Combatting Obesity?

A new mouse study shows promise in addressing the ongoing worldwide obesity epidemic. By targeting a specific brain molecule, researchers could be on the path to a therapy that would potentially enable patients to reduce calories while increasing exercise levels.

If Constantine A. Stratakis, MD, DSci, PhD, had his way, clinicians could soon offer their patients with obesity a nasal spray they could take every day that would not only entice them to exercise, but also avoid unhealthy foods. A lofty goal maybe, but endocrine science continues to reach new heights.

In a mouse study recently published in JCI Insight, Stratakis, chief of the Section on Genetics and Endocrinology at the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) at the National Institutes of Health (NIH), and his team found that by knocking out a single molecule in the brain — Prkar2a — the affected mice showed “decreased consumption of palatable, ‘rewarding’ foods and increased motivation for voluntary exercise.”

Exercise and a healthy diet remain the first line of treatment for patients with obesity, but the disease is still a global epidemic, and the numbers continue to climb. As the authors point out, increasing activity levels and decreasing caloric intake seems simple enough, but that regimen is not always an easy thing to follow, since there are “many opposing drives that are exacerbated by overscheduled sedentary lifestyles, changes in the food supply, and genetics.”

“It’s very significant for endocrinology that a small part of the brain experiences so specifically a single part of this major signaling pathway. And its inactivation leads to such a very robust phenotype.” – Constantine A. Stratakis, MD, DSci, PhD, chief, Section on Genetics and Endocrinology, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, Md.

So, the researchers turned to the brain — specifically an area that has been somewhat overlooked when it comes to metabolic dysregulation — the medial habenula (MHb). “This area is really intricately involved in reward pathway signaling, aversive stimuli and processing both positive experiences and negative. So, in that respect, it’s been studied in nicotine addiction, and withdrawal, depression, anxiety, a number of other mood related disorders,” says Edra London, PhD, a staff scientist in the Section on Genetics and Endocrinology at NIH, and lead author of the JCI Insight paper.

Here, we’ll take a look at what led London, Stratakis, and their team to looking at Prkar2a, the unexpected role the molecule plays in metabolic regulation, and what it could mean for patients who continue to struggle with obesity. “It’s an amazing phenotype because to my knowledge, there’s no other mouse, there’s no other animal model that has this highly desirable phenotype of wanting to exercise and avoiding dessert,” Stratakis says.

Obesity and Addiction Overlap

London, Stratakis, and the other authors of the JCI Insight paper write that the habenula is part of the brain responsible for reward processing, among other things – a part of the brain separated into two major subdivisions, the lateral Hb and the aforementioned MHb. Prkar2a is a molecule that codes for CAMP-dependent protein kinase (PKA) regulatory subunit IIα, and unlike other PKA subunits, Prkar2a is minimally expressed in the brain, except in the MHb.

Stratakis had already been studying PKA phenotypes in mice as they relate to cancer. However, when London arrived at Stratakis’s lab, she noticed that the mice that had Prkar2a deficiency (RIIα-knockout [RIIα-KO]) were not getting obese like the wild type mice. “My main interest was in obesity, metabolic dysfunction,” London says. “Interestingly, I’ve always been interested in where the overlap is between obesity and addiction. So, this mouse was kind of a gift in some ways.”

An initial study had London challenging different PKA mouse models with high-fat diets. She and her colleagues noticed that after chronic exposure to a high-fat diet, almost every mouse would become obese eventually. Some would stay lean for longer than others, but only to a certain point. The researchers eventually found that that RIIα-KO mice were regulating their caloric intake more. If given a choice, the RIIα-KO mice still preferred the high-fat diet to the dry, low-fat diet, but they seemed to moderate more. “When we actually systematically measured, we found out they actually were eating less,” London says.

That finding led the team to go further, so for this current study they gave the mice free access to running wheels and found that even though there are some mouse models where the animals become hyperactive at night, that was not the case here. The mice just seemed to take pleasure in running, whether they were receiving some kind of neurochemical reward for it, the authors aren’t sure. “That part isn’t completely clear yet, but it was a pretty interesting phenomenon to see along with the suppressed intake of a high-fat, palatable foods, and also sugar,” London says.

The fact that the mice seemed to enjoy running so much assuaged some of the worries the researchers had about anhedonia, since these mice were not eating as much, which could be a sign of an anxious or depressive state. London tells Endocrine News that she and her colleagues performed basic behavioral tests to look for anxiety, to see whether the mice were avoiding certain situations, but they found no signs of anxiety.

In fact, the only negative response the mice showed was when they were denied access to their running wheels. The researchers at one point put invisible locks on the wheels so the mice could get on the wheels, but they would not turn. “It was pretty interesting to see the parts of the brain that lit up with this immediate early gene expression,” London says.

Stratakis explains that they used a marker in the brain to track which parts lit up when the mice were denied the chance to run — parts of the brain that show anger.

“I mean, I kind of feel bad doing that,” London says.

Unlocking the Brain’s Secrets

Stratakis and London are careful to point out that this line of research may not be an answer to all types of obesity, but since Prkar2a is expressed in an area of the brain associated with addiction, targeting that molecule could provide some answers in disordered eating. Again, this is an area of the brain that has not been fully explored, but it could provide some insights into cravings and the overlap between addiction and obesity, in the same way that some people are susceptible to substance abuse when others aren’t. “It’s nice to see that PKA really has clearly such a big role in enough different cell types to kind of control these two really key behaviors in different directions,” London says.

This research is still relatively new, and Stratakis, London, and their team continue to look into the mechanistic explanations for this phenotype and phenomenon, from other molecules that are also expressed or continual release of rewarding chemicals that become reinforcing and change the brain chemistry. The newest functional magnetic resonance imaging should be sensitive enough to see what’s going on, but London says that would require collaboration with another lab.

London says that now they will look at the effects of a high-fat diet on a whole array of genes involved in dopamine, serotonin, and other neurotransmitters. “We’re trying to explore on a different front, looking a little bit at potential small molecule inhibitors, which I guess goes along the lines of the dream of a nasal spray one day,” she says.

“My main interest was in obesity, metabolic dysfunction. Interestingly, I’ve always been interested in where the overlap is between obesity and addiction. So, this mouse was kind of a gift in some ways.” – Edra London, PhD, staff scientist, Section on Genetics and Endocrinology, National Institutes of Health, Bethesda, Md.

“The idea is, if one came up with a short-acting inhibitor that would go directly to the brain, a nasal spray for example, and you wake up in the morning and you want to exercise but might not feel like it, you can take the nasal spray, your mood goes up, and you can go running,” Stratakis says.

For now, Stratakis hopes others will follow this research. He notes that the cyclic AMP signaling pathway has been studied extensively. As a result, it has received the most Nobel Prizes for medicine and physiology from any other hormonal signaling pathway. “It’s very significant for endocrinology,” he says. And cyclic AMP signaling has been widely exploited as a drug target for various therapeutic applications. “That a small part of the brain experiences so specifically a single part of this major signaling pathway. And its inactivation leads to such a very robust phenotype.”

“I think the differences we see really start to highlight some of the underlying differences in behavior, and how we respond to stimuli,” London says. “There is no end to the avenues to explore for this project since it seems to have relevance to diet-induced obesity and likely other behaviors related to the consumption of rewarding substances/activities.”

Bagley is the senior editor of Endocrine News. In the December issue, he wrote about the Endocrine Society’s notable accomplishments throughout 2020.

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