Obesity is a prevalent lifestyle disease that currently affects 42% of adults and 19% of children in the United States. [1] United States PDA-approved glucagon-like peptide-1 receptors (GLP-1R) are successful for diabetes and obesity treatments. However, its efficacy is limited by its side effects, such as nausea, vomiting, and malaise. Thus, there has been ongoing research to develop more efficacious treatments that can reduce or eliminate the side effects. 

The locus coeruleus (LC) of the brain is a site of action for GLP-1 signaling and a primary source of norepinephrine (NE) in the brain. Recent studies have demonstrated the role of the LC in modulating food intake. [2] Since LC has an established role in coordinating autonomic responses, the ability of LC Ex-4 to affect sympathetic and parasympathetic outflow is examined. Hence, the first component of the project is to delve into the physiological effects of Ex-4 and GLP-1.

The second component is to delve into the difference in neuronal activity in the LC of rats injected with Ex-4, GLP-1 or vehicle treatments. Studies have shown that Ex-4 is associated with enhanced c-Fos reactivity [3] because Ex-4 can cross the blood-brain barrier and reach the LC NE neurons more easily than the endogenous GLP-1. The project involves injections, brain slicing, immunohistochemistry, and fluorescent imaging to quantify the neuronal activity of Ex-4 and GLP-1 in rats. 

Results show that there are several physiological/ autonomic effects of Ex-4 and GLP-1, such as increased heart rate and body temperature (only for Ex-4), in addition to reduced food intake and body weight. In terms of neuronal activity, rats treated with Ex-4 had much greater c-Fos expression and thus neuronal activity. This can be explained by the fact that the Ex-4 is not degraded by how Ex-4 is not degraded by the enzyme dipeptidyl peptidase 4 (DPP4), which breaks down peptides like GLP-1.

This project’s data contribute to the growing body of evidence that LC is a feeding-relevant nucleus. LC GLP-1R activation suppresses food intake and leads to autonomic responses. For a long time, researchers have observed strange hyperglycemia in rats with Ex-4. Now, there is a site of action - the LC. This provides insight into the advancement of pharmacological treatments for obesity with more effective GLP-1 analogs and reduced side effects.

[1] Fortin, S. M., Chen, J. C., Petticord, M. C., Ragozzino, F. J., Peters, J. H., & Hayes, M. R. (2023). The locus coeruleus contributes to the anorectic, nausea, and autonomic physiological effects of glucagon-like peptide-1. Science Advances, 9(38). https://doi.org/10.1126/sciadv.adh0980  

[2] Fortin, S. M., Chen, J. C., Petticord, M. C., Ragozzino, F. J., Peters, J. H., & Hayes, M. R. (2023a). The locus coeruleus contributes to the anorectic, nausea, and autonomic physiological effects of glucagon-like peptide-1. Science Advances, 9(38). https://doi.org/10.1126/sciadv.adh0980 

[3] Kjaergaard, M., Salinas, C. B., Rehfeld, J. F., Secher, A., Raun, K., & Wulff, B. S. (2019). PYY(3-36) and exendin-4 reduce food intake and activate neuronal circuits in a synergistic manner in mice. Neuropeptides, 73, 89–95. https://doi.org/10.1016/j.npep.2018.11.004