Researchers have discovered a role played by a group of nerve cells in the brain in controlling food intake without causing nausea, which may open the way to developing obesity drugs with fewer side effects.
The study was conducted by researchers from the Monell Chemical Senses Center in the United States, and was published in the journal Nature this month, and was written about by the EurekAlert website.
The researchers described two distinct neural circuits that control the different effects of the same drug. The drugs studied are among the most effective weight-loss drugs available, known as long-acting peptide-1 receptor (GLP1R) agonists — which initiate neurochemical responses via receptors expressed in the body.
One of the most effective and popular GLP1-based drugs—called semaglutide and marketed as Ozempic® and Wegovy®—produces impressive weight loss results in clinical trials.
According to the World Health Organization, in 2022, 1 in 8 people worldwide were obese, making the development of such drugs crucial.
Nausea
“One of the barriers to drug treatment for obesity is side effects like nausea and vomiting,” said lead researcher Dr. Amber L. Alhadeff. “We didn’t have a good idea whether these unpleasant side effects were related to or necessary for the weight loss effects.”
To find out, the researchers investigated the brain circuits that link feeling full after a meal with avoiding food because of nausea. They found that neurons in the hindbrain mediate both effects of these obesity drugs, and they also unexpectedly discovered that the neurons that mediate satiety and nausea are different.
Two-photon imaging of GLP1R neurons in the hindbrain of living mice showed that most individual neurons are tuned to react to either nourishing or aversive stimuli, but not both.
Furthermore, the study revealed that GLP1R neurons in one part of the hindbrain called the area postrema respond more to aversive stimuli, while GLP1R neurons in another area called the nucleus tractus solitarius are more responsive to food stimuli.
Next, the team separately manipulated the two populations of GLP1R neurons to understand how they affected behavior. They found that activating neurons in the nucleus of the solitary tract led to satiety, but not any aversive behavior.
Path of aversion
Importantly, obesity drugs reduced food intake even when the aversion pathway was inhibited. These surprising findings highlight the number of neurons in the nucleus of the solitary tract as a target for future obesity drugs to reduce food intake without making individuals feel sick.
“Developing experimental obesity drugs that selectively activate this group may promote weight loss while avoiding aversive side effects,” the researcher said.
The concept of separating therapeutic and side effects at the level of neural circuits could, in theory, be applied to any drug that has side effects, the researchers said.