The next generation of obesity medications might work without making you feel sick, thanks to a new discovery by researchers at the Monell Chemical Senses Center. Their study, published today in Nature, has identified specific brain circuits that control feeling full separately from those that cause nausea, potentially paving the way for more effective and comfortable weight loss treatments.
Current popular obesity drugs, known as GLP1R agonists (including brands like Ozempic® and Wegovy®), have shown impressive results in clinical trials. However, many users experience unpleasant side effects like nausea and vomiting. With obesity affecting 1 in 8 people globally in 2022, according to the World Health Organization, finding better treatments is crucial.
“One of the barriers to drug treatments for obesity is side effects such as nausea and vomiting,” said senior author Amber L. Alhadeff, PhD, Monell Assistant Member. “We did not have a good idea of whether these unpleasant side effects are related or necessary for the weight-loss effects.”
Separating Satiety from Sickness
The Monell team investigated the brain circuits linking feeling full after a meal to those causing food avoidance due to nausea. They discovered that while neurons in the hindbrain mediate both effects, the individual neurons controlling satiety and nausea are different.
Using two-photon imaging in live mice, the researchers found that most individual neurons react to either nutritive or aversive stimuli, but not both. Furthermore, they identified two distinct areas in the hindbrain with different roles: the area postrema responds more to aversive stimuli, while the nucleus tractus solitarius leans toward nutritive stimuli.
Targeting the Right Neurons
The team then manipulated these two groups of neurons separately to understand their effects on behavior. Activating neurons in the nucleus tractus solitarius triggered satiety without causing aversion, while activating neurons in the area postrema triggered strong aversion.
Crucially, they found that obesity drugs could still reduce food intake even when the aversion pathway was inhibited. This discovery highlights the potential for developing new drugs that target only the satiety-inducing neurons, potentially eliminating the nausea side effect.
“Developing experimental obesity drugs that selectively activate this population may promote weight loss while avoiding aversive side effects,” said Alhadeff. The researchers suggest that this concept of separating therapeutic effects from side effects at the neural circuit level could potentially be applied to other drugs with side effects as well.
This breakthrough could lead to a new generation of obesity medications that are just as effective but much more comfortable for patients to use. By targeting only the neurons that control feelings of fullness, future drugs might help people lose weight without the constant nausea that plagues many current users.
As obesity rates continue to climb worldwide, this research offers hope for more effective and tolerable treatments. While further studies will be needed to translate these findings from animal models to human therapies, the identification of these specific neural circuits marks a significant step forward in the fight against obesity.
