A whole new generation of weight-loss treatments has transformed the treatment of obesity, helping people drop kilos at levels once considered difficult to achieve without surgery.
Injections like Ozempic, Wegovy and Mounjaro mimic a hormone known as GLP-1 that acts in various parts of the body to suppress appetite.
Though their effectiveness at helping people lose weight have made them blockbuster, these drugs have also been linked to side effects like nausea, vomiting, diarrhea, abdominal pain and constipation in some patients.
BRP, a 12-amino-acid appetite-suppressing molecule discovered by a team at Stanford Medicine in California, might help to achieve weight-loss effects with fewer drawbacks. It mainly acts in the part of the brain that regulates appetite, known as the hypothalamus.
How does BRP seem different?
Giles Yeo, professor of molecular neuroendocrinology at the UK Medical Research Council’s Metabolic Diseases Unit, told DW that, because of the blood-brain barrier, only two parts of the brain sense circulating hormones — the hypothalamus and the hindbrain.
“Ozempic and all of these gut hormones have their primary effect through the back of the brain,” he explained.
“The hypothalamus is the hunger sensor. It operates from dealing with starvation to no starvation. It’s trying to detect within your body. Am I starving or not? How hungry am I?”
“The hind brain does something different. It targets the visceral effect. It targets fullness, uncomfortably full: ‘Oh my God — I am Christmas full! I’m so full, I feel like puking.'”
Current weight-loss jabs do affect the hypothalamus, but they mostly target the hindbrain — and the feelings of fullness it generates. “The problem with targeting here is that the side effects are then nausea,” said Yeo. “In other words, the big reason why the side effects of these Ozempic-type drugs is nausea is because of the part of the brain it influences.”
BRP appears to act on a different pathway, affecting only the hypothalamus. That could lead to fewer unpleasant side effects. Another potential advantage of BRP is that in animal trials with the compound, mice appeared to lose fat but not muscle — another potential side effect of GLP-1 imitators.
‘Breathtaking’ search for a peptide
BRP could prove to be a big breakthrough, but just as groundbreaking was the way it was discovered.
In the search for alternatives to GLP-1 mimics, the Stanford researchers built an AI tool called Peptide Predictor that scanned about 20,000 human genes. It identified 2,683 potential hormone-like peptides — short chains of amino acids. The researchers whittled down candidates further and tested about a hundred of them.
BRP stood out as a winner. Obese mice given daily injections of the peptide lost weight, while untreated animals gained it.
“The sheer audacity to sort through the huge number of peptides is truly breathtaking,” said Randy J. Seeley, a professor of surgery at the University of Michigan in the US. “I am in awe of the work.”
How likely is a human BRP drug?
Katrin Svensson, the senior author of the Stanford study, has co-founded a company that plans to begin human clinical trials in the near future. But Seeley said it’s hard to predict whether success chalked up in animal trials will translate to humans.
“The hardest thing to know is whether a drug based on this will have adequate safety to become an approved obesity therapeutic,” he said. “Obesity is a chronic condition that needs to be treated chronically. That means such drugs need to be quite safe so that people can use them for a long time.”
GLP-1-type drugs are themselves adapted versions of a natural hormone — the modification just makes them last longer in the body. BRP could also be altered in a similar way.
Even if the compound were to make it through the necessary clinical human trials, GLP-1 mimics would likely still have clinical value as they have benefits beyond weight loss. For instance, they can reduce cardiovascular risk. But BRP would offer a valuable alternative in the midst of a growing crisis.
“The more tools we have to help us reduce our body weight, the more people are likely to find their personal mix,” said Yeo. “If you’re more likely to stay on the drug, you’re more likely to keep the weight off.”
“There are a billion people in the world with obesity, and more people die of obesity in the world now than die of actual famine,” he added. “It’s the first time in human evolution that we have actually reached this stage. And the more tools we have to treat obesity, the better.”