Inside Neuroscience: Separating GLP-1 Benefits From Side Effects

Glucagon-like peptide-1 (GLP-1) receptor agonists are fantastically popular drugs. People who take them report significant weight loss, as well as improvements in diabetes management, liver health, and even addictive behaviors. Despite these benefits, however, up to 50% of people stop taking the drugs within a year, in many cases due to severe side effects such as nausea, vomiting, and diarrhea. But while it may first appear that these side effects lie in the drugs’ actions on the gastrointestinal tract, scientists are increasingly looking to the brain for answers about both the benefits and downsides of GLP-1 drugs.

Lorenzo Leggio

“A lot of attention has been placed on the connections between the brain and the gut,” said Lorenzo Leggio, a physician-scientist at the National Institutes of Health. “Not only in terms of the gut microbiota and the vagus nerve, but also in terms of how hormones produced by the gut may signal to the brain and control appetite and hunger.”

Gut-produced hormones, like the naturally occurring GLP-1 peptide that current drugs mimic, may bind to multiple receptors in the brain, leading to several downstream effects. It’s plausible that GLP-1 drugs also bind to numerous receptors, which could drive both the positive and negative effects of the drugs.

“Fifty percent of the people who stop taking GLP-1 therapies do so because of side effects,” Leggio said. “As a consequence, it’s important to further understand the mechanism of GLP-1 therapies, not only in terms of their efficacy, but also in terms of their safety profile and side effects.”

In a press conference titled “GLP-1 Agonists: Addressing Side Effects of Weight Loss Drugs,” chaired by Leggio, scientists described how specific brain regions react to GLP-1 drugs, inducing not only weight loss, but also side effects such as vomiting, loss of thirst, and changes in pleasure-seeking behavior.

Nausea and Weight Loss: Inextricably Linked?

Because up to half of patients stop taking GLP-1s due to nausea and vomiting, scientists are keen to find ways to separate out which GLP-1-sensitive brain circuits produce the nausea and which drive weight loss.

Warren Yacawych

“In the brainstem, there are essentially two different areas that are incredibly sensitive to GLP-1s,” said Warren Yacawych, a graduate student at the University of Michigan. The area postrema (“effectively known as the brainstem’s ‘vomit center,’” Yacawych noted) is responsible for detecting and helping us eject ingested toxins. The nucleus of the solitary tract (or nucleus tractus solitarius, NTS), also located in the brainstem, monitors nutrient intake and helps us know when we’re full.

In a mouse model, Yacawych was able to selectively silence the GLP-1-sensitive cells in these regions. And while he found that the NTS was particularly important for weight maintenance in a normal physiological state, it was the area postrema that was responsible for weight loss on GLP-1 drugs.

Given that the “vomit center” is driving weight loss, “it’s very challenging right now to be able to separate these side effects, like nausea, from GLP-1’s intended effect,” Yacawych concluded.

“Love” and GLP-1s

James “Ernie” Blevins

GLP-1s aren’t the only hormone that can influence weight. James “Ernie” Blevins, a research biologist from the University of Washington and the Veterans Affairs Puget Sound Health Care System, has found that the “love hormone” oxytocin can also drive weight loss. However, while oxytocin does not appear to induce vomiting, its effects are also not as drastic as the effects of GLP-1 drugs. Blevins is exploring whether a combination of oxytocin and lower-dose GLP-1 drugs might maintain weight loss while reducing negative side effects.

Blevins and colleagues gave obese rats a subcutaneous pump with either oxytocin or a control. One week later, they gave the animals once-daily injections of low-dose tirzepatide, a GLP-1 receptor agonist drug. Alone, low-dose tirzepatide and oxytocin each produced approximately 7% loss of bodyweight. But together, the weight loss was additive, up to 11% of body weight.

“The combination treatment… tended to reduce fat mass, without causing any adverse or deleterious reductions in lean mass,” Blevins said. “I think that’s especially important for the geriatric population.”

In addition, Blevins and colleagues monitored for symptoms of nausea in rats, which typically look like a higher-than-usual consumption of clay as rats don’t have the ability to vomit. As with oxytocin alone, the combination treatment did not appear to cause nausea in the rats.

These initial studies used low doses of the GLP-1 drug. Higher doses, Blevins noted, can reach up to 20% weight loss. “The question is whether or not you can cut back on that dose and combine it with oxytocin and still achieve the 20–22% weight loss,” Blevins said. This is work that is still ongoing in his lab.

GLP-1s and Thirst

Dereck Daniels

One of the less-appreciated side effects of GLP-1 drugs is that in addition to reducing the drive to eat, they also reduce the drive to drink water. “This is particularly a problem when you think about the side effects that include vomiting and diarrhea,” said Dereck Daniels, a biologist at the University of Buffalo.

To better understand how GLP-1 drugs are reducing the thirst drive, Daniels is using a special rat called a “Brattleboro rat.” This unusual rodent lacks the hormone vasopressin, which helps the body retain water. As a consequence, the rat drinks more than seven times as much water as normal rats yet remains chronically dehydrated.

Daniels has found that while the Brattleboro rat responds normally to GLP-1 drugs in terms of food intake, it’s overly sensitive to the thirst-related side effects of the drugs. By looking carefully at which parts of the Brattleboro rat’s brain were affected by the GLP-1 drug, Daniels was able to identify the median preoptic nucleus, part of the hypothalamus, as a key area involved in the changes in thirst.

“If we start thinking about all the things that we want GLP-1 drugs to do, and the things we don’t want them to do, it now gives an opportunity to maybe design drugs that’ll target the good places and not the bad places,” Daniels said.

GLP-1s and the Brain’s Reward System

Ali Güler

Ali Güler, a biologist at the University of Virginia, is studying the effects of a newer class of GLP-1 receptor agonists — small molecules. These drugs may soon replace the injectable peptides that are currently more widely used. He has modified mice to carry a human version of the GLP-1 receptor specifically in the central amygdala, so that they respond to the GLP-1 drugs similarly to humans.

“If you give this drug to our humanized animals and give them a standard diet — this is equivalent to having a salad at lunchtime — the drug has no effect,” Güler explained. But if you provide a rewarding food — equivalent to a burger — the animals eat less than they normally would.

“One of the most surprising things that we found is that these drugs seem to be activating… and engaging the reward center of the brain,” Güler said. But “if the animals are on this drug, the dopamine release is greatly decreased,” Güler said, “essentially reducing the animal’s perception of how rewarding that food is.”

In addition to helping someone choose a salad over a burger, these drugs may also be useful in treating substance use disorder, something already seen with the peptide-based GLP-1 drugs, Güler noted.

When it comes to GLP-1 drugs, unraveling how different areas of the brain respond and in what way is a big challenge. “We don't understand at a biological level yet is how separable some of these feelings or behaviors are,” Yacawych said. “That's really what we're, as a field, trying to discover next.”