Peptide drugs that mimic glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) hormones have revolutionized weight-loss medicine. Now, a research team known for inventing the first GLP-1-GIP combination agonist has linked that peptide to a ligand for another target that is also hotly pursued in metabolic disease. The resulting conjugate molecule activates a whopping five receptors on the cell surface and in the nucleus—and in mice, it appears to offer a potent, safe treatment for obesity and diabetes (Nature 2026, DOI: 10.1038/s41586-026-10427-5).
GLP-1 is the most famous peptide hormone, but it is just one member of the appetite-regulating incretin family. The GLP-1-mimicking drug tirzepatide also goes after GIP, and Eli Lilly and Company is also taking polypharmacology even farther. Retatrutide, which activates GLP-1, GIP, and glucagon receptors is in late clinical development. And at a conference in June, Lilly-funded scientists are expected to share preclinical data on a quintuple agonist that activates receptors for all three incretins along with two other peptide hormones, amylin and calcitonin.
Meanwhile, peroxisome proliferation-activated receptors (PPARs) are obesity drug targets in their own right: activating them can reduce inflammation and restore insulin sensitivity. But molecules that activate PPARs often have side effects. “They are very powerful. The problem is they act on too many cells, also in cells where they have detrimental effects,” says Timo Müller at the Helmholtz Zentrum München.
Müller was part of the team that developed the first GLP-GIP combination peptide and the first incretin triple agonist, though other groups commercialized the molecules that became today’s blockbuster GLP-1 drugs. His research group has also experimented for years with conjugates that combine incretin-mimic peptides with nuclear hormones such as estrogen. Could the same be done for PPAR?
Müller and his team started with lanifibranor, an agonist for PPAR alpha, gamma, and delta that is in clinical development for fatty liver disease, and linked it to a GLP-1-GIP mimic peptide using a pH-sensitive linker. After the molecule binds to GLP-1 and GIP receptors, cells internalize it. Then a pH change cleaves the linker, freeing the lanifibranor moiety to escape to the nucleus and activate PPARs.
“This is a very creative design,” Chun-Xia Yi, a neuroscientist who studies obesity signaling in the brain at UMC Amsterdam, says in an email to C&EN. “These researchers are well-known experts in making such multi-agonist drugs in obesity.”
The researchers linked pan-PPAR agonist lanifibranor (pictured) to a peptide that activates receptors of GLP-1 and GIP for a multivalent conjugate molecule.
The Helmholtz researchers compared obese mice treated with their conjugate molecule to mice treated with the unconjugated peptide and lanifibranor components at the same dose. They found the conjugate boosted weight loss and insulin sensitivity, without raising the safety concerns associated with PPAR agonists. They also found that the conjugate has distinct effects on the activity and protein expression of the hypothalamus, a brain region that regulates satiety and is key to the effects of GLP-1 drugs.
Finding out just which of those effects derives from which of the molecule’s targets will be a difficult task. “We know very little about how GIP works in the brain, and we know almost nothing about PPARs in the brain,” Müller says. To understand its activity completely, he says, scientists would need to test it in mice lacking all five target receptors—an impossible task.
Whether the molecule will remain so robust in humans is yet to be determined. “From a translational perspective, rodent obesity models often tend to amplify efficacy signals compared to humans,” Yi says. She also wonders whether the drug’s effects will persist after dosing is complete.
Still, if the quintuple agonism approach takes off, it could signal a new chapter in the incretin saga. Li Qiang, a pharmacologist at Peking University, tells C&EN in an email that the work “sets a new benchmark in the treatment landscape.”
Müller thinks the new molecule has potential to become a front-line treatment for diabetes and obesity. “When you have massive weight loss without effects in lean mice, this is the point at which you call your patent officer,” he says.
CORRECTION
This story was updated on April 30, 2026, to correct Chun-Xia Yi’s gender. She is a woman.
Laurel Oldach is a senior editor and life sciences reporter at C&EN.
2026 American Chemical Society
