The blockbuster obesity drugs work mostly one way. Semaglutide ↗ and tirzepatide ↗ make people eat less. A receptor called NK2R does something those drugs barely touch: in animals, switching it on also makes the body burn more energy. A paper published this week in Nature Structural and Molecular Biology ↗ takes aim at the single problem standing between that biology and a usable drug.
NK2R, short for neurokinin 2 receptor, sits on cells in the brain and in peripheral tissue. In 2024 a group led by Zachary Gerhart-Hines at the University of Copenhagen reported in Nature ↗ that activating it suppresses appetite through the brain and raises energy expenditure through the body at the same time, while improving insulin sensitivity. In diet-induced obese mice and in obese macaques, a long-acting selective agonist cut food intake and body weight and pushed up oxygen consumption and fat burning. The spin-out built around that work, Embark Biotech, was bought by Novo Nordisk.
Here is the catch. The body's own switch for NK2R is a peptide called neurokinin A ↗, and it is sloppy. It also turns on close relatives in the same receptor family, including the receptor for substance P ↗, the peptide that carries pain and inflammation signals. Hitting those off-target receptors is how you get side effects. A neurokinin drug that is not selective is not a drug.
How a peptide picks one receptor
Neurokinin peptides are read by their receptors in two parts. The tail end of the peptide flips the receptor on, and the front end decides which receptor in the family it talks to. The new paper works out, at the structural level, what makes an agonist choose NK2R over its siblings, which is exactly the information you need to design a molecule that activates the weight-loss receptor and leaves the others alone. The natural ligand cannot do that. An engineered one can be built to.
A selective, long-acting NK2R agonist, referred to as EB1002 in a recent review ↗, is the version carried furthest, with a half-life long enough to imagine once-weekly dosing like the GLP-1 drugs. No human trial has been reported yet.
Why the field cares
The interest in NK2R is really interest in energy expenditure. Every approved obesity drug works by turning appetite down, and appetite has a floor. People can only eat so much less, which is part of why weight loss on these drugs plateaus. A drug that also raises the rate at which the body spends energy attacks the other side of the equation. That is the prize, and selectivity is the toll. peptidemodel tracks NK2R as TACR2 ↗ and the off-target it has to dodge as TACR1 ↗; the GLP-1 receptor ↗ drugs it would complement sit one target over.