By investigating how new-generation obesity drugs affect food intake in relation to nausea, researchers have identified specific neurons in the brain that regulate eating habits without causing unpleasant side effects in animal studies.
The latest research on cutting-edge obesity medications may focus on the connection between feeling full after a meal and how the brain processes feelings of sickness. Researchers from the Monell Chemical Senses Center have isolated a group of brain neurons that manage food intake without inducing nausea in a model using these medications.
The findings, detailed in a current publication in the journal Nature, outline the distinct neural pathways that control different aspects of the same medication. These drugs, categorized as long-acting glucagon-like peptide-1 receptor (GLP1R) agonists, trigger neurochemical reactions through receptors in the body.
One particularly effective GLP1-based medication, known as semaglutide and commercially available as Ozempic® and Wegovy®, has shown significant success in weight loss trials. With the World Health Organization reporting that 1 in 8 individuals worldwide grappled with obesity in 2022, the development of such drugs becomes increasingly crucial.
Dr. Amber L. Alhadeff, a senior researcher at Monell Chemical Senses Center, explained, “One challenge in using drugs to combat obesity lies in the side effects like nausea and vomiting. We needed to understand if these adverse effects were connected to or necessary for the weight-loss benefits.”
To address this question, the Monell team delved into the brain circuits that link satiety from eating with the aversion to food caused by nausea. The study revealed that hindbrain neurons are responsible for both responses to these obesity medications and surprisingly found that the neurons associated with feeling full differ from those linked to feeling sick.
Using advanced imaging techniques in live mice, the researchers observed that most hindbrain GLP1R neurons reacted specifically to either nourishing or unpleasant stimuli, but not both. Furthermore, the study disclosed that GLP1R neurons in the area postrema region were more responsive to negative stimuli, while those in the nucleus tractus solitarius area leaned towards positive stimuli.
The team then separately manipulated the two sets of GLP1R neurons to analyze their impact on behavior. They observed that stimulating neurons in the nucleus tractus solitarius led to a sense of fullness without any aversive reactions, whereas activating neurons in the area postrema triggered strong adverse responses. Notably, the obesity drugs decreased food intake even when the aversion pathway was blocked. These unexpected results underscore the importance of targeting neurons in the nucleus tractus solitarius to develop future obesity medications that curb food intake without causing discomfort.
Alhadeff commented, “Creating experimental obesity drugs that selectively activate this neuronal population may aid in weight loss without inducing adverse effects.” The researchers added that the concept of segregating therapeutic effects from side effects at the neural circuit level could potentially be applied to various medications with unwanted effects.
In addition to Alhadeff, the study’s co-authors include Kuei-Pin Huang, Alisha A. Acosta, Misgana Y. Ghidewon, Aaron D. McKnight, Milena S. Almeida, Nathaniel T. Nyema, Nicholas D. Hanchak, Nisha Patel, Yenoukoume S. K. Gbenou, and Kevin A. Bolding from Monell, and Alice E. Adriaenssens from University College, London. Alhadeff, Bolding, Ghidewon, and McKnight also have affiliations with the Penn Medicine Department of Neuroscience.
This research received support from various organizations including the National Institutes of Health, the American Heart Association, New York Stem Cell Foundation, Klingenstein Fund, Simons Foundation, Pew Charitable Trusts, National Science Foundation, Penn Institute for Diabetes, Obesity, and Metabolism, and Monell Chemical Senses Center. The study also utilized a confocal microscope obtained through an NIH instrumentation grant. Alhadeff is recognized as a New York Stem Cell Foundation Robertson Investigator and a Pew Biomedical Scholar.
