Even before the era of GLP-1 weight loss drugs, Wake Forest University neuroscientist Wayne Pratt dedicated his research lab to better understanding how the brain regulates food motivation.

Now, with GLP-1s a household name, his research has even greater and more immediate implications: We know that drugs like Ozempic, developed to treat diabetes because they lower blood sugar, also suppress appetite. But we don’t know exactly how and why they work. 

GLP-1 receptors are distributed throughout the brain, and Pratt studies a region, the nucleus accumbens, that promotes overeating of tasty foods. If his research can help us understand how GLP-1 drugs affect those receptors to suppress the motivation to eat—as well as the “food noise” many GLP-1 users describe—it could lay the groundwork for the next generation of therapies for obesity and overweight.

“GLP-1s have only been around for a little over a decade, and we’re still only beginning to understand how their activation leads to changes within the brain’s motivational circuits,” he said. “But basic science takes time and meticulous effort. We have a lot of work ahead of us.”

What’s next? GLP-1 isn’t the only peptide, or signaling molecule, that helps the brain communicate with the gut. Pratt and his research team have begun exploring how manipulating molecules like gastrin-releasing peptide (GRP) might alter eating behavior. 

Here, Pratt explains how food motivation works in the brain and where GLP-1 drugs fit in. 

What do you mean by food motivation and how do you study it?

My students and I are interested in how the brain directs motivated behavior, particularly towards foods. We eat for a variety of reasons, including because we’re hungry, because food tates good, because we have memories around foods. 

How much we eat is also determined by how hard it is to get the food. Using rats as our animal model, we examine how different brain regions and neurotransmitters impact motivation towards food. My lab is particularly interested in the nucleus accumbens, which is a region of the brain that promotes overeating in response to particularly rewarding foods.

Motivation can be broken up into at least two components. One is appetitive motivation, or the drive that comes ahead of reaching your goal object. We measure that in rats by asking how much they might be willing to work to get a food item. 

In our lab, we often have them press a lever to get sugar pellets. We ask them how motivated they are to earn those pellets by gradually increasing the number of lever presses they need to get one. At some point, the cost is too high and they stop pressing, and that gives us an indication of how motivated they are to earn food. 

The second part of motivation is the consummatory aspect, which is when you have the goal object in front of you and now you’re engaging with it. In humans and animals, we measure consummatory motivation by giving them food and then measuring how much they eat. 

Both appetitive motivation and consummatory motivation can be regulated by things like hunger and palatability. You might be willing to work harder for your favorite ice cream and eat more of it than you would for a bowl of carrots, but you’ll work even for carrots if you’re hungry enough.

How do the concepts of adaptive and maladaptive eating play a role?

When we talk about adaptive eating, we’re talking about eating that takes care of our energy needs in a manner that is good for our general health and wellbeing. So if we’re hungry, we might eat a larger meal. And sometimes if we’re not hungry, we might eat a larger meal. But the adaptive nature of it is such that in our next meal we may eat less food. Overall, things balance out. 

Maladaptive eating has deleterious consequences to our health or our interactions with other people. Overeating to the extent where we gain lots of weight can impact our health, and that may be considered maladaptive. It can be caused by a number of things, ranging from being in an environment with lots of hyperpalatable foods to having changes in our brain circuitry that detect the signals that indicate whether we’ve had enough food or not. 

Binge eating is also maladaptive eating, and that often gets cued by foods that are high in sugar, salt and fat. But restricting our dietary intake to the point where it impacts our health is also a form of maladaptive eating. 

That distinction is important to my research because the same circuits that drive adaptive eating can, under different circumstances, lead to maladaptive eating. If we can better understand what triggers those things, then we can better develop therapies that target maladaptive eating. 

What have you learned about how GLP-1 drugs work in the brain to suppress appetite and lead to weight loss?

In 2020, a former student of mine, Zak Pierce-Messick, examined the role of GLP-1 receptors in the nucleus accumbens on the intake of a sweetened-fat diet in rats. Think of this diet as the inside of an Oreo cookie, but not quite as sweet. 

We were interested in whether GLP-1 receptor activation of this brain region would inhibit eating. We also knew that if we injected a drug to activate the mu opioid receptor in the nucleus accumbens, we could promote binge-like feeding with rats. (The mu opioid receptor blocks pain signals and drives the euphoria that can contribute to opioid drug addiction.) 

Interestingly, within the nucleus accumbens, the GLP-1 receptor activation didn’t reduce the feeding on its own, but it significantly reduced the binge-like effect that was caused by the opioid receptor stimulation. 

Why might this matter? In the news right now, it’s hard to miss the talk about food noise—that pull that certain people seem to have towards foods and overeating. GLP-1 receptor agonists like Wegovy and Ozempic appear to turn down that noise in human beings. We can’t ask what’s going on in the rat’s mind, of course, but our study did suggest that GLP-1 receptors within the nucleus accumbens may turn down the powerful effect that opioid receptors have in promoting overeating.

How do GLP-1 receptor drugs work in the brain? 

That is a big question, and we really don’t understand the answer to that yet. 

This is some of what we know: GLP-1 receptors are distributed throughout the brain and particularly in regions of the brain that are important for motivation. The drugs, at least in a limited manner, penetrate the brain, particularly in those areas that are known to help us detect energy stores and needs within the body. Dopamine circuits, which are important for appetitive phases of motivation, are regulated by GLP-1 receptors, and that may change the amount of effort that animals are willing to put in to work for food. 

That being said, GLP-1 receptors are also throughout the whole body, and there may be indirect effects of GLP-1 receptors in the periphery that then get signaled to the brain. So rather than viewing these drugs as having an effect on a single appetite center in the brain, it might be more accurate to say that GLP-1 receptors are distributed throughout brain regions that are involved in food motivation, processing the palatability of food, and directing our behavior towards food. 

Exactly what the effects are of GLP-1 drugs on the brain networks involved in motivation is something that we’re still working to understand.

What are the challenges to developing an effective weight loss drug that doesn’t have serious side effects?

When we manipulate one part of the brain, like we do in my lab, the effects are not only happening in that part of the brain. If we block receptors in the nucleus accumbens, for example, that’s going to change how the nucleus accumbens processes information and what signals it ultimately sends on to the rest of the brain. So when we manipulate one brain region, we’re tweaking the rest of the circuit, and that has implications on behavior. 

Understanding how the different neural pieces fit together in an interconnected whole helps us to better parse out different phases of motivation, understand how different neurotransmitters promote different types of motivated behaviors, and lead to treatment strategies that hopefully impact the motivation we’re interested in while not causing unwanted side effects.

The medical community has been trying to treat obesity for a number of years with pharmacological approaches, but any drug that you take has side effects. 

• Early attempts at treating obesity with drugs focused on amphetamine-like drugs. They caused modest weight loss consistent with appetite suppression, but they also led to dependence and abuse, and therefore they were taken off the market. 
• In the 1990s and early 2000s, new drugs that targeted serotonin and norepinephrine were developed. One of them that was particularly effective was called fen-phen. It was on the market for less than two years. One of the two components that went into that drug led to heart valve defect. 
• Following up on that was sibutramine, which was effective for modest weight loss and which was on the market for 11 years. But if you lose weight, you hope that your cardiovascular risk drops. And it turned out that after long periods on this drug, people were developing higher cardiovascular risk. 
• Following that was rimonabant, which was a cannabinoid receptor antagonist on the market in Europe for a short time. It caused people to lose appetite and lose weight, but it was withdrawn from the market after some psychiatric problems developed as side effects. 

These side effects indicate how challenging it is to try to tackle one thing—food motivation—without having impacts on other body systems. 

That is part of what makes GLP-1 drugs so interesting. They were originally developed to treat diabetes, and the side effect was weight loss. They’re now being used to treat weight loss, but we’re really only at the beginning of understanding how they are accomplishing that. Much remains to be discovered about how they work and what side effects they may lead to.

What do you want everyone to understand about food motivation?

Motivation isn’t any one thing. With regards to food, we’re driven by hunger, by palatability, we’re driven by our memories. And how much we eat depends upon how hard it is to get the food that we’re after. 

That last part is particularly useful. If food is easier to obtain, you’re more likely to eat it. If you increase the effort, you may eat less of it. So if you have ice cream in your freezer, you’re more likely to eat some than if you were to have to walk down to the corner and buy an ice cream cone.

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