GLP-1 from the distal gut is dispensable for body weight and glucose regulation but slows small intestinal transit in female mice.

Enteroendocrine cells (EECs) are specialized cells located throughout the gastrointestinal (GI) tract, where they have an essential role in regulating various physiological processes related to digestion, metabolism, and gut physiology. EECs secrete different hormones in response to food intake and the presence of nutrients in the gut, which regulate digestion, appetite, insulin secretion, and energy balance. One of the most well-studied hormones is glucagon-like peptide-1 (GLP-1), which is produced by L cells in both the small intestine and the colon. Colonic GLP-1-secreting L cells are not immediately exposed to food and are thus less likely to be responsible for the release of GLP-1 that occurs shortly after ingestion of a meal. Here we sought to determine the role of GLP-1 produced from the distal gut, by generating mice with a deletion of the gene encoding proglucagon (Gcg) in the distal gut and analyzed the effects on body weight, glucose metabolism, and gut transit. Deletion of Gcg in the distal gut reduced circulating levels of GLP-1 but did not affect glucose metabolism or insulin levels on a chow diet or body weight gain or glucose metabolism on a Western-style diet. However, we observed that deletion of distal gut GLP-1 resulted in faster small intestinal transit in female but not male mice. We successfully developed a mouse model that can target L cells in the distal gut and demonstrate that GLP-1 from the distal gut is dispensable for weight and glucose regulation, whereas it regulates gut motility in female mice.NEW & NOTEWORTHY Previous studies have suggested that GLP-1 from the distal gut may be of importance for regulation of glucose metabolism although the contribution from ileal and colonic GLP-1 has not been separated. In this study, we established a mouse model to more specifically dissect the role of colonic GLP-1 and demonstrate that the physiological role of GLP-1 from the colon does not include the well-established metabolic functions but rather slows small intestinal transit.