Over the last few years, the number of people taking glucagon-like peptide-1 (GLP-1) receptor agonists — medications traditionally used to treat type 2 diabetes for weight loss has greatly increased. A recent poll found that 12% of Americans about 1 in 8 adults — have taken a GLP-1 medication.
While only certain GLP-1 medications are FDA-approved to treat obesity, others are being used off-label for their weight loss benefits. A common side effect of taking GLP-1 medications is nausea. Now, Monell Chemical Senses Center researchers have identified a specific population of neurons in the brain they believe may hold the key for GLP-1 drugs to suppress appetite without nausea. The study was recently published in the journal Nature. For this study, researchers used a mouse model to look for a neurological connection between GLP-1 medications and the side effect of nausea.
The majority of people who take these drugs experience nausea at some point — some have it more severe than others. But because it is the most prevalent side effect of GLP-1 medications, we were really interested in understanding whether the appetite suppression and weight loss stem from the same or different neural circuits as those that mediate the nausea,” Alhadeff said.
Scientists focused on hindbrain GLP-1R neurons, which Alhadeff said are a population of neurons at the back of the brain that express the receptor that binds GLP-1 drugs like Ozempic and Wegovy. Researchers discovered that this population of hindbrain GLP-1R neurons is the main drug target that mediates the appetite suppression and weight loss effects of GLP-1 drugs. During the study, Alhadeff and her team found that in mice the individual GLP-1R neurons are calibrated to react to stimuli that are either nutritive or nourishing, or aversive or unpleasant.
Additionally, researchers found that GLP-1R neurons in the area of the hindbrain known as the area postrema respond mostly to unpleasant stimuli, while those in a different area called the nucleus tractus solitarius are most likely to acknowledge nourishing stimuli. Interestingly, activation of the area postrema GLP-1R neurons causes nausea, but activation of nucleus tractus solitarius GLP-1R neurons causes satiety without nausea. The implication is that there is a neuron population — nucleus tractus solitarius GLP-1R neurons that can decrease appetite and cause weight loss without making individuals feel sick and so we hope that this finding will lead to the development of more selective weight loss drugs.
Nausea is a common side effect of GLP-1 medications, affecting approximately 30-40% of patients. It is usually mild and transient, but it can be severe enough to lead some patients to discontinue treatment. Anything that can reduce side effects for medications is a good idea. One thing that they’re not really considering is some of the nausea is because the medications (slow down) emptying of the GI tract. And that’s one of the benefits of the medication — when the stomach is emptying slower, the patient stays full for longer and that also contributes to the weight loss. So, if one eliminates that effect of the medication, then the medication may not be as effective.
