Brain scientists are seeking weight-loss drugs without the nausea : Shots

Millions of Americans have lost weight using drugs like Wegovy and Zepbound.

But people taking these drugs often experience unpleasant side effects.

“They are losing weight, which is a positive thing,” says Warren Jakavich from the University of Michigan, “but they experience such severe nausea and vomiting that patients stop treatment.”

So at this year's Society for Neuroscience meeting in San Diego, Jakavich and other researchers held a session to describe their efforts to understand and address the problem of side effects.

Weight loss products are called GLP-1 agonists. They act by mimicking a hormone that reduces appetite and slows digestion.

Jakavich and his colleagues wanted to know if they could tweak these drugs to suppress appetite without making people sick.

The team focused on two areas of the brainstem that are particularly affected by GLP-1 drugs.

“The first of these is affectionately called the vomiting center of the brainstem,” Jakavich says. “It is naturally designed to detect any accidentally ingested toxin and coordinate the feeling of nausea and the vomiting response.”

The second area monitors food intake and tells people when they are full.

The team found a way to target GLP-1 to the area responsible for the feeling of fullness, while preventing the drug from reaching the center of vomiting.

When the researchers did this, the mice no longer felt sick. But they also didn't lose weight, likely because there are special cells in the vomiting center that don't cause vomiting but are crucial for weight loss.

“So it’s very difficult,” Jakavich says, “to separate these side effects, such as nausea, from the putative effects of GLP-1, such as weight loss.”

A possible workaround was suggested by a team led by Ernie Blevins University of Washington. They gave obese rats a low dose of the drug GLP-1 along with the hormone. oxytocinwhich itself suppresses appetite. This allowed the rats to lose weight without feeling nauseated.

Not just nausea

Another side effect of GLP-1 drugs is a decrease in thirst, which can be dangerous for people who are already losing a lot of fluid due to side effects such as vomiting and diarrhea.

“If you're dehydrated and don't feel like replacing those fluids, that's going to be a problem,” says Derek Daniels from the University at Buffalo.

To understand how GLP-1 drugs reduce thirst, Daniels and his team began studying the brains of rats. And they were lucky.

“We had a lucky break in the lab,” Daniels says. “And a happy accident happened to a rat named Brattleboro rat“

Brattleboro rats are laboratory rodents with a genetic mutation that makes them thirsty almost constantly. But the scientists found that these rats were also very sensitive to the GLP-1 drugs, which dramatically reduced their water intake.

The team studied the brains of rats to see how GLP-1 affects thirst. This led them to several areas of the brain that appear to influence thirst, but not appetite.

The discovery could help scientists preserve thirst by developing drugs that “target the good places rather than the bad places,” Daniels says.

Appetite and addiction

A team from the University of Virginia found that GLP-1 drugs already affect an area of ​​the brain that plays a role not only in eating but also in addiction. This is an area associated with emotions and the reward system.

When researchers delivered GLP-1 to this area of ​​the brain in mice, it reduced their desire for “healthy foods like hamburger,” says Ali D. Guler University of Virginia.

But the animals continued to eat healthy, non-nutritive foods, he says, much in the same way that people prefer the salad bar to dessert.

Identifying this brain region should help scientists find GLP-1 drugs that target the reward system while avoiding areas associated with appetite, Guler says. And it could lead to new treatments for alcoholism and other substance use disorders.

This finding may also explain the observation that people taking GLP-1 agonists tend to reduce their alcohol consumption.