# The Role of Pancreatic Preproglucagon in Regulating Local Inflammation in Mice

## TL;DR

This study shows that pancreatic GLP-1 helps control local inflammation in the pancreas during severe inflammation, especially in obese mice.

## Contribution

The study reveals a novel immunological role of pancreatic GLP-1 in regulating local macrophage accumulation during inflammation.

## Key findings

- Obesity increases the satiety and inflammatory responses to LPS and boosts pancreatic GLP-1 production.
- Pancreatic Gcg is essential for limiting local macrophage accumulation and inflammation in response to LPS.
- Macrophages in the pancreas express GLP-1R, indicating a direct regulatory role of pancreatic GLP-1 in inflammation.

## Abstract

What are the main findings?
Obesity increases the satiety and inflammatory responses to exogenous LPS and increases the production of pancreatic GLP-1.Pancreatic Gcg is necessary for restraining the local inflammatory environment in response to LPS.

Obesity increases the satiety and inflammatory responses to exogenous LPS and increases the production of pancreatic GLP-1.

Pancreatic Gcg is necessary for restraining the local inflammatory environment in response to LPS.

What is the implication of the main finding?
Pancreatic production of GLP-1 increases with inflammatory stress and is necessary for limiting local macrophage accumulation and inflammation.Expression of the GLP-1R on macrophages suggests that pancreatic production of the GLP-1R functions to regulate the local inflammatory environment.

Pancreatic production of GLP-1 increases with inflammatory stress and is necessary for limiting local macrophage accumulation and inflammation.

Expression of the GLP-1R on macrophages suggests that pancreatic production of the GLP-1R functions to regulate the local inflammatory environment.

Data suggest that both pancreatic and intestinally produced glucagon-like peptide-1 (GLP-1) increases in response to inflammation. Here, we set out to determine the tissue-specific function of increased GLP-1 during inflammatory stimuli. Using our innovative mouse model of tissue-specific Gcg (the gene that encodes GLP-1) expression, we explored the function of GLP-1 under severe inflammatory conditions induced by lipopolysaccharide (LPS) administration in lean and obese mice. High-fat diet (HFD) increased the LPS-induced suppression of feeding and increased the plasma levels of pro-inflammatory cytokines and GLP-1. Both pancreatic and intestinal Gcg expression contribute to LPS-induced increases in GLP-1, but Gcg was not necessary for the glucoregulatory or suppressed feeding responses to LPS. While Gcg was not necessary for systemic cytokine increases with LPS in either chow- or HFD-fed mice, whole-body Gcg-null animals had increased macrophage accumulation and an increased expression of genes reflecting pro-inflammatory signaling in the pancreas. We then performed flow cytometry on the pancreas from mice expressing a fluorescent marker on the GLP-1 receptor (GLP-1R). In response to LPS, we found that pancreatic CD64+/CD11b+ macrophages expressed the GLP-1R. We conclude that under severe inflammatory conditions, pancreatic production of GLP-1 functions in an immunological rather than a metabolic role to directly regulate local macrophage accumulation.