Can Gene Suppression Help Patients Struggling With Diabetes and Obesity?

Addiction centers LHb and MHb play a role in both conditions

With Edra London PhD

Obesity Gene

 

Is food addicting? Is obesity a disorder of the brain? Bidirectional signaling along the gut-brain axis would suggest that obesity involves multiple systems working in concert that can transition “eating to live” into “living to eat.” One small brain structure, the habenula, seems to be involved in the decision making process to engage in or avoid these motivational behaviors.

Habenula is Latin for “little rein,” which is rather descriptive of the small bilateral nuclei sitting above the thalamus. The habenula integrates signals from the reward neural circuitry with signals from sensory, cognitive, and emotional processing structures. It evaluates the inputs of each and then nudges the likelihood of a behavior one way or the other.

There are two main habenular (Hb) divisions: the lateral habenula (LHb) and the medial habenula (MHb). In anticipation of an aversive outcome or when we anticipate losing out on a reward, the LHb becomes highly active. In anticipation of something desirable or when we anticipate avoiding a punishing event, the LHb decreases its activity. In light of this, the LHb can be thought of as the “anti-reward” nuclei.

The role of the LHb in addiction, including food addiction, is much better understood than its diminutive partner, the MHb. However, a recent study by London et al. sheds light on the MHb and found it might be rather important in the development of food addiction, obesity, and energy balance as well.

How genes affect eating habits

The prkar2a gene codes for a protein kinase A (PKA) subunit, RIIa, expressed exclusively in the neurons and glia of MHb. We reached out to lead researcher, Edra London PhD at the Eunice Kennedy Shriver National Institute for Child Health and Human Development to find out why the prkar2a gene was important. She told us, “Prkar2a is a new regulatory target that can potentially modify two of the behaviors at the heart of maintaining energy balance: intake of palatable or rewarding foods and the motivation to exercise.”

In a recent study by London and colleagues, the researchers knocked out the prkar2a gene in mice. Prkar2a knock-out (KO) mice had decreased levels of both basal and cAMP-stimulated PKA activity in the MHb, whereas PKA activity remained intact in other brain areas.

KO mice and their wildtype littermates underwent motivational behavior testing to evaluate the reward of highly palatable food and the motivation to consume it. Mice were also evaluated in an exercise task to look at non-food rewards.

Eating to live versus living to eat

In this next task mice were first fasted to 90% of body weight and then trained to press a lever for food. Both the wild-type and the prkar2a–KO mice learned the task effectively, suggesting that both types of mice found the food pellet rewarding. However, as the reward payout became fewer and farther between in a progressive payout ratio, the KO mice earned fewer pellets and stopped engaging in lever pressing earlier than the wild-type mice. In other words, the wild-type were indulging their appetitive motivation even after achieving satiety, while the KO mice stopped. The authors conclude that the reward circuitry remains active in KO mice though they exhibited a moderate appetitive motivation.

Sex differences in preferences for savory or sweet

This “moderation” phenotype of prkar2a KO mice was further tested using highly palatable stimuli, and either a high-fat diet or sugar water. Mice were given free access to a high-fat diet for three weeks. During this time, wild-type mice significantly increased their caloric intake as did the male KO mice. Female KO mice did not, maintaining their original body weight, and suggesting that they were less motivated to indulge in the high-fat diet.

The rewarding effects of sweets revealed another gender difference. In this test, animals had free access to both standard water and 10% sucrose water. On the first day, all the animals showed a preference for the sugar water, with at least 80% of their liquid intake coming from the sugar water bottle. On subsequent days, the wild type mice continued drinking most of their daily intake from the sugar water (80-100%), as did the female KO mice, (>80%). As a result, all three groups gained weight during this time. The researchers found that weight gain was directly related to the calories ingested from the sugar water and was not a result of increased food intake.

The male KO mice still showed a preference for the sugar water, as indicated by >50% of their liquid intake coming from the sugar water, but they also spent more time drinking from the standard water bottle compared to any other group, suggesting they were less motivated to drink the sweet water. Furthermore, the KO males did not gain weight but still ate the same relative volumes of chow.

In an anthropomorphic interpretation, reduced MHb PKA activity reduced the motivation to pursue food reward when it required more effort. When food was highly palatable and freely accessible, reduced PKA activity made the high-fat diet less motivating to female mice and sweet rewards became less motivating to males. The sexual differences in taste preferences have also been observed in humans. Men tend to have a greater preference for fat and salty foods than womenand even in light of negative consequences, men still prefer these foods.

In humans though, the drive to eat is more complex than just taste preferences. We are motivated to eat for emotional, cultural, and social reasons, and each reason comes with its own food preferences. Dr. London told Endocrine Web, “Sex differences in eating behaviors, taste preference, reward signaling, addiction, depression and more have become clearer in the recent years as a result of the push to include both male and females in basic research. It is fascinating to see how sex is so impactful on eating behaviors and preferences.”

Seeing exercise as a reward

In the final motivational test, London et al. gave the mice access to a running wheel. Both male and female KO mice had significantly more wheel turns than wildtype mice. It was not that these animals were more active, as home cage activity was similar between all animals. Neither did they spend more time on the wheel or run more often on the wheel. The KO mice simply ran faster and worked harder, charting significantly more wheel turns than their wildtype siblings.

To understand the rewarding effect of exercise, researchers locked the running wheels so that the equipment was still present but not functional. They then assessed stress markers, c-fos, and jun-fos in the MHb. KO mice prevented from running had significantly higher expression levels of both stress markers than the wildtype mice who were prevented from running. Thus, exercise was a much more rewarding behavior for the prkar2a-KO mice than the wild-type mice, and prevention from exercising had substantially more negative effects on that group.

How genes affect our motivations toward food or exercise

Lastly the researchers wanted to see if reinstating PKA activity in the MHb would abolish the “moderation” phenotype. To do this, they used recombinant adeno-associated virus (rAAV) coding for the prkar2a gene and stereotaxically injected it into the MHb of both wild-type and prkar2a KO mice. Animals underwent the same behavior testing paradigms.

In the presence of palatable foods, AAV-injected KO mice were as motivated to push levers, eat, and drink as their wild-type littermates. In addition, wheel running became less motivating. The addition of prkar2a-rAAV in wild-type mice did not change how they interacted with the rewarding stimuli. Thus, prkar2a expression has reversible influence over motivational behaviors that help mice maintain energy balance.

How hunger hormones like ghrelin affect energy balance and food addiction

The balance between energy intake and energy expenditure is the first line of defense in obesity. Increasing physical activity, decreasing sedentary behaviors, and improving diet are the initial approaches most people use to lose weight, however some studies suggest that long term weight loss should also address the shared risk factors between obesity and food disorders. Food addiction, unlike drug addiction, requires involvement of the digestive system, not just the brain.

Information about hunger and satiety are transmitted from the gut to the brain via autonomic and endocrine messengers (i.e. ghrelin, insulin, GLP1, and peptide YY), some of which are received in the hypothalamus. From there the “feeding” messages are passed onto other brain areas, but one area of interest is the interpeduncular nucleus (IPN), a small nucleus at the base of the midbrain. It is here that input from the MHb and hypothalamus combine and decisions about eating are ultimately formed.  

Data from the London study supports the notion that the MHb is directly involved in integrating information about energy balance , as well as the cognitive and emotional processes that lead to decisions concerning behavior seeking or avoidance decisions that can lead to food addiction. We asked Dr. London what the clinical application might be. She replied; 

“We are planning a collaboration aimed at identifying potential small molecule inhibitors of the protein that prkar2a codes for, PKA RIIα. If an inhibitor can have the same effect as the deletion of the gene in mice, it will open the possibility of future therapeutic use.”

The takeaway: The ability to pharmaceutically turn down the motivation to eat and increase the motivation to exercise could one day provide a powerful weapon in combating obesity, and the resulting increase in diabetes that often accompanies it.

The authors declare no competing interests. Funding for the study was provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Division of Intramural Research.

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