Scientists identify brain area that holds two groups of neurons: one for pre-meal sensations of fullness and one for post-meal satiety

How blockbuster obesity drugs create a full feeling — even before one bite of food

Scientists identify brain area that holds two groups of neurons: one for pre-meal sensations of fullness and one for post-meal satiety

People taking Ozempic and similar weight-loss drugs often feel full even when they sit down to a meal and haven’t taken a single bite. Now scientists have found a brain region that is involved in this effect — and that also helps to cause the same sensation without the use of weight-loss drugs.

In a paper published today in Science¹, scientists describe two distinct groups of neurons associated with feeling full: one for pre-meal fullness and one for post-meal fullness. The study also shows that the blockbuster obesity drugs act on those ‘fullness’ neurons, but more research is needed to determine the drug’s exact mechanism, the authors say.

The identification of these two populations of neurons is the paper’s key contribution, says Allison Shapiro, a specialist in neurodevelopment at the University of Colorado Anschutz Medical Campus in Aurora who was not involved in the resarch. It fits in with the anecdotal idea that there are two types of fullness: one that is anticipatory and another that arises in response to eating. “Based on what they've found, it appears that this specific region of the hypothalamus is responsible for both, which is pretty cool.”

Fullness without food

The latest blockbuster medications for obesity mimic a hormone called glucagon-like peptide 1 (GLP-1), which controls blood-sugar levels and also acts on the brain to curb appetite. The GLP-1 drugs include semaglutide, sold as Ozempic and Wegovy, and liraglutide, sold as Saxenda and Victoza.

Hyung Jin Choi, a neuroscientist at Seoul National University and one of the authors of the study, experienced the effects of liraglutide firsthand when he took the drug for obesity. “I felt a huge increase in fullness when I saw and smelled food, even before I started eating,” he says. This motivated him to dig into this feeling of pre-meal fullness.

He and his colleagues recruited people with obesity and asked them to report their level of satiation before exposure to food; while seeing a delicious plate of Korean fried chicken but before eating it; and after eating. People taking liraglutide had a feeling of fullness even before exposure to food, but this feeling grew when they were shown food and grew again after they’d eaten. The findings demonstrate that Choi isn’t the only one on this drug who feels full at the mere sight of food — a feeling that the team named ‘preingestion satiation.’

In contrast, for participants who weren’t taking the drug, satiation decreased at the sight of the fried chicken and didn’t rise again until after they’d eaten.

To identify the exact region in the brain responsible for these sensations, researchers homed in on an area called the dorsomedial hypothalamus (DMH). Its neurons have GLP-1 receptors, allowing GLP-1 to act directly on this brain region.

The researchers artificially stimulated DMH neurons in mice that were in the middle of a meal and found that the animals immediately stopped eating. When these neurons were chronically activated, mice ate less; when these neurons were chronically inhibited, mice ate more. The results suggest that the region plays a central part in satiation.

Neurons that signal ‘I’m stuffed’

With that established, the authors investigated the activity of individual neurons in the mouse DMH. They identified two distinct populations of neurons: one that was consistently active from the moment mice started seeking food to the moment they started eating and another that was consistently active only as the mice ate.

The authors also showed that GLP-1 drugs act on this specific brain region. In mice that received liraglutide, neural activity in the DMH area was higher before and during meals than in mice that hadn’t received the drug. The team deleted GLP-1 receptors in some animals’ DMH neurons, curbing the ability of liraglutide to act on this brain area. These mice ate more than those that didn’t have their GLP-1 receptors deleted, signalling that liraglutide’s ability to suppress appetite had been weakened.

Karolina Skibicka, a neuroscientist at Penn State in University Park and at the University of Gothenburg, in Sweden, notes that other studies have found no such changes in feeding behavior after manipulation of GLP-1 receptors in this brain area. One possible explanation might be related to the discovery reported in the paper of two distinct neuron populations in the DMH. “We tend to think of GLP-1-receptor-expressing neurons in a given brain area as this homogeneous population playing the same role,” she says. “This paper is showing that that's clearly not true. It’s just one brain area, but GLP-1 receptors on neurons are doing different things there.”

The study showed a congruence between what was seen in humans and in mice, says Amber Alhadeff, a neuroscientist at the Monell Chemical Senses Center in Philadelphia, Pennsylvania. She notes it's becoming increasingly important to use clinical observations to inform the basic science studies on GLP-1 drugs. “But then it’s also important to go back and subsequently confirm the existence of these mechanisms in humans. This paper was a nice example of taking that in both directions.”

doi: https://doi.org/10.1038/d41586-024-02106-0

This story originally appeared on: Nature - Author:Mariana Lenharo