To understand a weight-loss drug, scientists mapped a brain circuit older than humanity

Millions of people around the world have benefited from the first generation of modern weight loss drugs, which can help some people lose up to 25 percent of their body weight and improve their overall health.

What’s remarkable is that scientists aren't sure how these drugs work. They know that the drugs influence how the brain regulates appetite. But they still aren’t sure which specific cell populations the drugs target.

Now, scientists at the University of Copenhagen and their collaborators have pinpointed the precise brain circuits behind the appetite-lowering effects of a new class of weight-loss drugs. The research was published in Nature Metabolism.

Not all of today's therapies suit everyone. The more precisely we understand how these drugs act, the better we can design treatments with fewer side effects and that help people keep the weight off after they stop.

"But the discovery also tells us something about being human. These appetite circuits sit deep in the brainstem, an evolutionarily ancient territory we share with rats and macaques. They are so deeply hardwired that it's little wonder trying to eat less can feel like fighting millions of years of evolution," he adds.

Hunting for the cells that respond

The first generation of modern weight-loss drugs relied solely on targeting the brain receptors for the naturally occurring hormone GLP-1. One of these drugs, semaglutide, can lower body weight by more than 15%. Synthetic versions of another natural hormone, amylin, can also reduce weight, but only by up to 12%. Combining the two, however, increases the weight loss effect to over 20%.

Both semaglutide and the amylin analogue, cagrilintide, work on the brain, specifically the brainstem, but far less is known about the specific cells that cagrilintide acts on. So the Pers Group and their collaborators first created a detailed cross-species map of every cell type in the dorsal vagal complex, the small brainstem region amylin depends on to work.

To build it, they used single-nucleus RNA sequencing, a technology that reads which genes are switched on inside individual cells to reveal each one's identity. Applied to over 530,000 cells from mice, rats, and macaques, they identified 80 distinct types of neurons. Then they used a second technology to pinpoint exactly where each cell type is located within the brainstem.

With the map in hand, they went hunting for the cells that respond to the drug. Giving cagrilintide to rats and mice and watching for neurons that switched on, they found two populations that lit up. One of them, in a region called the NTS, responded to long-term treatment in rats but stayed quiet in mice. This was a clue because cagrilintide drives lasting weight loss in rats but has little effect in mice. Then they tested these neurons to see if they were truly responsible for the weight loss.

While the neurons in the first area, called the area postrema, only had a temporary effect on appetite, those in the NTS were essential for cagrilintide to induce weight loss. When activated by cagrilintide, these cells send a signal that leads to weight loss. When they switched off the Prlh gene that encodes the signal, cagrilintide largely lost its ability to curb appetite and reduce weight.

Cagrilintide quiets appetite not by acting on the brain in some diffuse way, but by speaking to one specific population of neurons in the NTS. Tellingly, these are the very neurons the drug fails to engage in mice, which may be exactly why it barely works in them.

A circuit we share, but not exactly

What makes the finding matter beyond rats is where these cells sit. They live in the brainstem, one of the most ancient corners of the brain that has remained almost unchanged for hundreds of millions of years and across species as distant as mice and macaques. And when the team looked in human brainstem tissue, the same Prlh neurons were there too.

But not exactly. The neurons in rats are tuned to respond to slightly different signals to those in humans and macaques. So, while the circuit that cagrilintide leans on in a rat clearly has a counterpart in us, it's not certain that it listens in quite the same way.

It's a reminder that even deeply conserved machinery can be wired differently from one species to the next. We have to map it carefully before assuming that what works in a rat will work in a person. Still, this research uncovered something new about the brain, and about the deep evolutionary roots of appetite itself. Knowledge we'd never have gone looking for if we weren't trying to work out how these drugs do their job.

This paper was a collaboration between the University of Michigan, the Oregon National Primate Research Centre, and Novo Nordisk A/S.

Read the article in Nature Metabolism here: A cross-species atlas of the dorsal vagal complex reveals neural mediators of the effects of cagrilintide on energy balancev