Millions of Americans have successfully lost weight with medications such as Wegovy and Zepbound, but the experience is often accompanied by significant side effects. “They lose weight, which is a positive thing,” says Warren Yacawych of the University of Michigan, “but they experience such severe nausea and vomiting that patients stop treatment.” To address this challenge, Yacawych and fellow researchers presented a session at this year’s Society for Neuroscience meeting in San Diego, outlining their work to better understand and reduce these adverse effects.
These medications belong to a class called GLP-1 agonists, which mimic a natural hormone that suppresses appetite and slows digestion. The researchers aimed to determine whether these drugs could be modified to curb hunger without causing queasiness. Their focus was on two regions of the brain stem that respond strongly to GLP-1 drugs.
“The first is affectionately known as the brain stem’s vomit center,” Yacawych explains. “It’s naturally designed to detect any accidentally ingested toxin and coordinate the feeling of nausea and the vomit response.” The second area helps regulate food intake, signaling fullness. By directing GLP-1 drugs specifically to the area controlling satiety while avoiding the vomit center, the team prevented nausea in mice. However, the mice did not lose weight, likely because certain cells in the vomit center—while not directly triggering vomiting—are essential for weight loss. “So it’s very challenging,” Yacawych adds, “to be able to separate these side effects, like nausea, from GLP-1’s intended effects, like weight loss.”
A potential solution emerged from research led by Ernie Blevins of the University of Washington. His team administered a low dose of a GLP-1 drug to obese rats alongside the hormone oxytocin, which itself suppresses appetite. This combination enabled the rats to lose weight without experiencing nausea, providing a promising avenue for future therapies.
Understanding Other Side Effects
GLP-1 drugs can also reduce thirst, which poses risks for people already experiencing fluid loss due to vomiting or diarrhea. “If you’re in that state of dehydration and you’re not feeling thirsty to replace those fluids, that would be a problem,” warns Derek Daniels of the University at Buffalo. To investigate this effect, Daniels and his team studied rat brains, making an unexpected discovery. “We had a happy accident in the lab,” he recalls. “And the happy accident involved a rat called the Brattleboro rat.”
Brattleboro rats possess a genetic mutation that makes them extremely thirsty, but the researchers found these rats were also highly sensitive to GLP-1 drugs, which significantly decreased their water intake. Further examination of the rats’ brains revealed areas influenced by GLP-1 that affect thirst without impacting appetite. Daniels notes this finding could allow future drugs to target beneficial brain regions while avoiding negative ones, preserving hydration while still aiding weight loss.
GLP-1, Appetite, and Addiction
Additional research from the University of Virginia highlights the broader effects of GLP-1 drugs on the brain. GLP-1 appears to act on regions involved in both the reward system and emotion. When the researchers delivered GLP-1 to this area in mice, it reduced their interest in highly rewarding foods, such as burgers, while leaving their consumption of healthier foods unchanged. “Rewarding food, like a burger,” says Ali D. Güler of the University of Virginia, “was less appealing, but the animals continued to eat healthy, nonrewarding foods,” a dynamic comparable to humans opting for a salad over dessert.
Pinpointing this brain region may enable the development of GLP-1 drugs that target the reward system while avoiding areas directly controlling appetite. Güler explains that this could not only aid weight management but also contribute to treatments for alcoholism and other substance use disorders. The research also aligns with observations that people taking GLP-1 agonists often reduce their alcohol consumption.
Conclusion
Advances in understanding how GLP-1 drugs interact with different brain regions are helping scientists design therapies that promote weight loss without common side effects like nausea or decreased thirst. Research in both animal models and brain mapping is paving the way for more targeted medications that could improve overall safety and effectiveness for patients.
