The next chapter in the story of the popular obesity drugs could focus on the physiological relationship between feeling satisfied after a meal and the neurological control of nausea. By teasing apart the therapeutic benefits from the adverse effects of these drugs, researchers at the Monell Chemical Senses Center found in an animal model a population of neurons in the brain that control food intake without causing nausea.
The study, published today in the journal Nature, describes two different neural circuits that control different effects of the same drug. The drugs studied are among the most effective weight-loss drugs available – known as long-acting glucagon-like peptide-1 receptor (GLP1R) agonists – which initiate neurochemical responses via receptors expressed in the body.
One of the most effective and popular GLP1-based medications – called semaglutide and marketed as Ozempic® and Wegovy® – produces impressive weight loss results in clinical trials. According to the World Health Organization, 1 in 8 people worldwide would be obese by 2022, making the development of these types of drugs of great importance.
“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 adjunct member. “We had no good idea whether these unpleasant side effects were related or necessary to the effects of weight loss.”
To find out, Monell’s team examined the brain circuits that link feeling full after eating a meal and those that cause food avoidance due to a feeling of nausea. The researchers found that neurons in the hindbrain mediate both effects of these obesity drugs, and unexpectedly also found that the individual neurons that mediate satiety and nausea are different.
Two-photon imaging of hindbrain GLP1R neurons in living mice showed that most individual neurons are tuned to respond to stimuli that are either nurturing or aversive, but not both. In addition, the study revealed that GLP1R neurons in a part of the hindbrain, called postrema of the area respond more to aversive stimuli, while GLP1R neurons in another area called the core tractus solitarius tend towards nutritional stimuli.
The team then manipulated the two groups of GLP1R neurons separately to understand their effects on behavior. They found that activating neurons in the nucleus tractus solitarius causes satiety, without aversion behavior; while activating neurons in the postrema area produces a strong aversion response. Importantly, the obesity drugs reduced food intake even when the aversion pathway was inhibited. These surprising findings highlight the population of neurons in the nucleus tractus solitarius as a target for future obesity drugs to reduce food intake without making individuals feel ill.
“Developing experimental anti-obesity drugs that selectively activate this population could promote weight loss while avoiding aversive side effects,” Alhadeff said. In fact, the authors say, the concept of separating therapeutic effects and side effects at the level of neural circuits could theoretically be applied to any drug with side effects.
In addition to Alhadeff, co-authors are first author Kuei-Pin Huang, Alisha A. Acosta, Misgana Y. Ghidewon, Aaron D. McKnight, Milena S. Almeida, Nathaniel T. Nyema, Nicholas D. Hanchak, Nisha Patel, Yenoukoume SK Gbenou and Kevin A. Bolding, all of Monell, and Alice E. Adriaenssens of University College, London. Alhadeff, Bolding, Ghidewon and McKnight are also affiliated with the Penn Medicine Department of Neuroscience.
This work was supported by the National Institutes of Health (R00DK119574 and DP2AT011965), the American Heart Association, New York Stem Cell Foundation, Klingenstein Fund and Simons Foundation, Pew Charitable Trusts, National Science Foundation (Grant2236662), the Penn Institute for Diabetes, Obesity and Metabolism, and the Monell Chemical Senses Center. The confocal microscope used in these studies was purchased with an instrumentation grant from the NIH (S10OD030354). Alhadeff is a Robertson Scholar at the New York Stem Cell Foundation and a Pew Biomedical Scientist.
