Messing With Brain Proteins Made Ozempic-Like Drugs More Effective, Less Nauseating

The weight loss drugs that have become wildly popular in recent years could become more effective in the future, including a possible reduction in side effects, new research suggests.

Semaglutide, part of a family of drugs called GLP-1, was first approved by the FDA for the treatment of type 2 diabetes in 2017, but it wasn’t until 2021 that the drug was cleared as a weight-loss treatment. Demand for semaglutide, sold under the brand names Ozempic, Rybelsus, and Wegovy, as well as another GLP-1 drug called tirzepatide (more commonly known as Mounjaro and Zepbound) soon soared, with one poll published in May finding that one American adult in eight had been prescribed a GLP-1 at some point. Numerous celebrities began sharing their weight loss efforts that involved the drug or others like it, including Oprah, Kelly Clarkson, and Charles Barkley. 

But these drugs don’t work for everybody, and they can come with some unpleasant and even dangerous side effects. One recent study of semaglutide’s effectiveness in weight loss found that seven out of 12 male test subjects responded to the drug, compared to 24 out of 28 women. That same study found that over half the test subjects showed some kind of adverse reaction, such as nausea, constipation, abdominal pain, or diarrhea, though in most cases those side effects were classified as mild to moderate. A much larger study, published in the Journal of the American Medical Association last year, found that use of the drug was linked to increased risk of pancreatitis, bowel obstruction, and gastroparesis, a disorder where the movement of food from the stomach to small intestine is obstructed. (Read more: What to Know About the Link Between Stomach Paralysis and Ozempic)

Researchers at the University of Michigan believe they may have found a solution in the form of proteins in the nervous system. The proteins, named melanocortin 3 and 4, are mostly found on the surface of brain neurons that are important for regulating eating and balancing your body’s energy. Inhibiting MC3R or boosting MC4R in mice that were also given a GLP-1 drug was found to boost weight loss by up to five times compared to mice that only received GLP-1 drug. The results were published Monday in the Journal of Clinical Investigation.

“We found that activating the central melanocortin system hypersensitizes animals to the effects of not just GLP-1s, but to every anti-feeding hormone we tested,” said study co-author Roger Cone in a press release.

They also looked at parts of the mice’s brains that are believed to be connected to nausea when taking GLP-1 and found no increased activity when those proteins were stimulated, while mice who were only given the drug did show a significant jump in that part of their brains. 

Coincidentally, a completely different study published last week also showed promise in reducing nausea on the drug, though that research is also just in mice—whether it’s applicable to people remains unknown.

While it’s not clear when, if ever, drugs that could mimic the experiment could be made available to the public, Cone said he’s optimistic his results in mice would also hold true for humans. “The melanocortin system is highly conserved in humans,” he said in the release. “Everything we’ve observed in the mouse over the past decades studying these proteins has also been found in humans, so I suspect that these results would also be translatable to patients.”