By separating the therapeutic benefits from the adverse effects of known obesity drugs, researchers at the Monell Chemical Senses Center found a population of neurons in the brain that controls food intake without causing nausea in animal models. The study, published in the journal Nature, describes two distinct neural circuits that control different effects of the same drug. The drugs studied are among the most effective weight loss drugs known as long-acting agonists of the glucagon-like peptide 1 receptor (GLP1R), which trigger neurochemical responses via receptors expressed in the body.

Neurons that Mediate Satiety and Nausea Act Differently

One of the most effective and popular GLP1-based drugs – called semaglutide and marketed as Ozempic® and Wegovy® – achieved impressive weight loss results in clinical trials. Obesity is a worldwide problem, with more and more people struggling with excess weight. One of the obstacles to treating obesity with medication is side effects such as nausea and vomiting, according to the study’s lead author, Amber L. Alhadeff, PhD, Monell Assistant Member. The researchers did not have a good idea of whether these unpleasant side effects were related to or necessary for weight loss.

To find out, the Monell team examined the circuits in the brain that link the feeling of fullness after eating a meal to the circuits that cause food avoidance due to nausea. They found that neurons in the hindbrain mediate both effects of these anti-obesity drugs and, surprisingly, also discovered that the individual neurons that mediate satiety and nausea are different.

Neuron Population in the Nucleus Tractus Solitarius As a Target for Future Obesity Drugs

Two-photon imaging of GLP1R neurons in the hindbrain of living mice showed that most individual neurons are tuned to respond to either nutritive or aversive stimuli, but not to both. In addition, the study found that GLP1R neurons in one part of the hindbrain, called the area postrema, are more responsive to aversive stimuli, while GLP1R neurons in another area, the nucleus tractus solitarius, are more responsive to nutritive stimuli.

Next, the team manipulated the two groups of GLP1R neurons separately to understand their effects on behavior. They found that activation of neurons in the nucleus tractus solitarius elicited satiety without aversion behavior, while activation of neurons in the area postrema elicited a strong aversion response. Importantly, the anti-obesity drugs reduced food intake even when the aversion pathway was inhibited.

These surprising results suggest that the population of neurons in the nucleus tractus solitarius (brain region responsible for taste perception) could be a target for future obesity drugs to reduce food intake without making people feel sick. Developing experimental obesity drugs that selectively activate this population could promote weight loss while avoiding aversive side effects. In fact, according to the authors, the concept of separating therapeutic and side effects at the neural circuit level could theoretically be applied to any drug with side effects.