Andrew Hardaway, Ph.D., and Miguel Duran, Ph.D.A new study led by Andrew Hardaway, Ph.D., associate professor in the University of Alabama at Birmingham Department of Psychiatry and Behavioral Neurobiology, provides new insight into how GLP-1 medications suppress appetite by acting on specific brain circuits.
Published in the peer-reviewed journal Molecular Metabolism, the research sheds light on how the central amygdala (CeA)—a region of the brain involved in emotion, motivation and behavior—is activated by GLP-1 drugs and plays a critical role in their appetite-suppressing effects.
GLP-1 medications, taken to treat obesity and Type 2 diabetes, mimic glucagon-like peptide 1, a naturally occurring hormone that helps regulate blood sugar, slows stomach emptying, and promotes feelings of fullness. While previous studies consistently showed that GLP-1 drugs activate the CeA, the mechanism behind that response was unclear.
“Here, we provide new mechanistic insight into this phenomenon. Systemic GLP-1 analog administration results in a rapid and lasting activation of the CeA,” Hardaway said.
Key findings
Using optical recordings in mice, researchers confirmed that GLP-1 treatment activates the CeA. They then used chemogenetic techniques to selectively shut down CeA activity and found that GLP-1 drugs were significantly less effective at reducing food intake.
“We found that the GLP-1 analog didn’t work as well,” Hardaway said. “Activation of the CeA was required for the full appetite-reducing properties of a systemic GLP-1 analog.”
The team identified three distinct cell populations within the CeA and discovered that two help mediate the appetite-suppressing effects of GLP-1 drugs. One population expresses protein kinase C delta, while the other expresses the GLP-1 receptor (GLP-1R).
The GLP-1R-expressing neurons played a modest role when mice ate standard chow. However, they became much more important when mice were offered a high-fat diet. When researchers inhibited these neurons, mice consumed significantly more high-fat food despite receiving a GLP-1 drug.
Broader implications
According to Hardaway, the study’s most significant finding is that activation of the CeA appears to be essential to how GLP-1 medications reduce appetite.
“The amygdala is usually thought of as the brain’s fear center, but it has a much broader role in emotional processing,” Hardaway said. “This activation is actually key to reducing appetite.”
The findings raise the possibility that GLP-1 drugs may influence emotional processing as well as eating behavior, potentially helping explain some psychological effects reported by patients taking GLP-1s.
What’s next
Hardaway’s lab plans to further investigate how GLP-1 receptor-expressing neurons in the amygdala contribute to the effects of systemic GLP-1 drugs and whether these pathways influence other behaviors.
“Some of these cells in the amygdala have already been shown to mediate valence—how good or bad something is perceived,” Hardaway said. “Our work could inform broader changes in emotional processing that may affect fear learning, reward, or even social behavior.”
The study’s first author was Miguel Duran, Ph.D. Additional UAB contributors included Ningxiang Zeng, Elam J. Cutts, Anusha Polamarasetty, Melissa Rodriguez, and Kirk M. Habegger, Ph.D.
Hardaway is an associate scientist in multiple UAB research centers, including the Comprehensive Diabetes Center, Comprehensive Neuroscience Center, Nutrition Obesity Research Center, and Civitan International Research Center.