Study Suggests TUB-PAG Pathway Has Role in Regulation of Feeding Behavior

A new study from Northwestern Medicine has uncovered a potential reason why some people struggle to feel full after eating, which can contribute to obesity. Researchers discovered a structural brain connection involved in regulating feeding behavior. The weaker this connection, the higher an individual's body mass index (BMI) tended to be.

The connection lies between two key brain regions—the olfactory tubercle (TUB), part of the olfactory cortex involved in the brain's reward system, and the periaqueductal gray (PAG) in the midbrain, which plays a role in motivated behaviors like suppressing eating when full.

Previous work showed that food smells are appealing when hungry but less so after eating to fullness. This suggests the sense of smell guides eating motivation, which should be modulated by hunger and satiety signals. However, the neural basis for this was unclear.

"The desire to eat is related to how appealing food smells," explained Guangyu Zhou, lead author of the study published in the Journal of Neuroscience. "If brain circuits connecting reward areas to behavior areas are disrupted, eating may remain rewarding even when full, leading to overeating."

The researchers hypothesize that in healthy individuals, strong connectivity between the TUB and PAG allows satiety signals to effectively switch off the rewarding value of food smells after eating, suppressing further intake. Weaker connections may impair this process.

Using MRI data from the Human Connectome Project, the team found that weaker structural connectivity between these regions correlated with higher BMI across a large sample. This relationship was replicated in a separate smaller dataset.

"When this circuit is weaker, a person may not get 'stop signals' that eating doesn't feel good anymore after feeling full," said senior author Christina Zelano. "They may keep eating despite lack of hunger."