Published Mar 01, 2026 | 7:00 AM ⚊ Updated Mar 01, 2026 | 7:00 AM
Representative image.
Synopsis: Three of the most widely used GLP-1 weight-loss drugs—semaglutide, tirzepatide and retatrutide—have been found to work in a rare, treatment-resistant genetic form of obesity, a new study in mice has found. Over three weeks, the drugs lowered food intake, improved liver health and reduced cholesterol, with tirzepatide producing the greatest weight loss.
Picture being stuck in a car with failing brakes, rolling down a hill. No matter how hard you push the pedal, it has no effect. For people born with a genetic mutation in the hypothalamus, the loss of control over their body can feel just like that.
MC4R, a receptor in the hypothalamus, is key to regulating food intake and body weight. Mutations in one of the pathways that lead to the receptor can cause a loss of control.
Children with this mutation tend to develop early-onset obesity. By adulthood, no matter what intervention they might have tried, the situation would hardly have changed.
A study published in the International Journal of Obesity suggests those patients may soon have a treatment.
Researchers tested three of the world’s most talked-about weight-loss drugs—semaglutide, tirzepatide and retatrutide—on mice engineered to lack the MC4R gene entirely. The drugs worked. “Our findings demonstrate that all three GLP-1 analogs exhibit significant anti-obesity effects in MC4R KO mice,” the authors wrote.
The body regulates hunger by sending a chain of signals along pathways known as POMC-MC4R and leptin-MC4R as the stomach nears fullness.
Mutations anywhere along this chain can cause some of the most treatment-resistant forms of obesity known to medicine.
GLP-1 drugs—the class that includes the active ingredient in Ozempic and Wegovy—work by routing the message to receptors across the brain, the pancreas and the vagus nerve, which runs from the brainstem into the abdomen.
The team’s question was direct: if you remove the receptor—MC4R—entirely, do these drugs still work?
MC4R knockout mice ate far more than normal mice, gained fat rapidly and developed fatty livers, elevated cholesterol and early insulin resistance, mirroring what clinicians see in patients with MC4R pathway deficiency.
Researchers administered each drug once daily by injection for 21 days.
All three drugs worked. Semaglutide cut body weight by an average of 19.7 percent. Retatrutide cut 24.1 percent. Tirzepatide, which targets two receptors rather than one, produced the most striking result: a 31.6 percent reduction.
These mice had no functioning MC4R, yet the drugs still worked.
Food intake fell across all three groups. Liver injury markers fell. Cholesterol and triglycerides dropped. Inside the liver, genes that drive fat production switched off.
“These results suggest that GLP-1 analogs may provide an effective treatment option for patients with MC4R-POMC pathway deficiencies,” the authors noted.
The researchers believe the drugs reached the brain through routes that do not pass through MC4R at all.
“GLP-1 analogs appear to exert their anti-obesity effects through central pathways that do not involve MC4R, as well as via peripheral mechanisms involving the vagus nerve,” they wrote. Tirzepatide adds a second receptor target—GIP—which may explain why it outperformed the others.
For clinicians treating a child with POMC deficiency or Prader-Willi syndrome, this matters. The only drug approved for some of these conditions, setmelanotide, works by nudging the very pathway these patients lack. Its results have been modest. GLP-1 drugs carry no such dependency.
The study also found that all three drugs reduced not just fat mass but lean mass. The authors flag sarcopenia—loss of muscle mass and strength—as a risk that rises with longer treatment.
“Chronic suppression of food intake could lead to muscle loss, potentially resulting in sarcopenia,” they wrote, adding that “combination strategies, possibly including agents that preserve or increase muscle mass, may help mitigate this effect.”
The study ran for three weeks, used only male mice and lost two animals from the tirzepatide group before the end. No human trial has yet tested these drugs in patients with MC4R mutations. The mice offer proof of concept, not a prescription.
“This study provides the first demonstration that GLP-1 analogs can be effective in treating obesity associated with MC4R deficiency,” the authors said.
