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Researchers discover neurons in the brain that controls food intake without causing nausea in an animal model

By teasing apart the therapeutic benefits from the adverse effects of glucagon-like peptide-1 receptor (GLP1R) agonists, researchers from the Monell Chemical Senses Center found a population of neurons in the brain that controls food intake without causing nausea in an animal model.

The research describes two distinct neural circuits that govern different effects of the same drug. The drugs studied are among the most effective weight-loss drugs available, which initiate neurochemical responses via receptors expressed in the body.

"One of the barriers to drug treatments for obesity is side effects such as nausea and vomiting," said senior author, Dr Amber L Alhadeff, 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."

To find out, the Monell team investigated the brain circuits that link feeling full after ingesting a meal to those causing food avoidance due to feeling nauseated. The researchers found that neurons in the hindbrain mediate both effects of these obesity drugs, and unexpectedly also discovered that the individual neurons mediating satiety and nausea are different.

Two-photon imaging of hindbrain GLP1R neurons in live mice showed that most individual neurons are tuned to react to stimuli that are either nutritive or aversive, but not both. The study revealed that GLP1R neurons in one part of the hindbrain called the area postrema respond more to aversive stimuli, whereas GLP1R neurons in another area called the nucleus tractus solitarius lean toward nutritive stimuli.

Next, the team separately manipulated the two groups of GLP1R neurons to understand their effects on behaviour. They found that activating neurons in the nucleus tractus solitarius triggers satiety, with no aversion behaviour; whereas, activating neurons in the area postrema trigger a strong aversion reaction.

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 sick.

"Developing experimental obesity drugs that selectively activate this population may promote weight loss while avoiding aversive side effects," said Alhadeff. In fact, the concept of separating therapeutic and side effects at the level of neural circuits could, in theory, be applied to any drug with side effects.

The findings were reported in the paper, 'Dissociable hindbrain GLP1R circuits for satiety and aversion', published in the journal Nature.


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