| First Author | Panaro BL | Year | 2020 |
| Journal | Mol Metab | Volume | 37 |
| Pages | 100990 | PubMed ID | 32278655 |
| Mgi Jnum | J:302482 | Mgi Id | MGI:6508154 |
| Doi | 10.1016/j.molmet.2020.100990 | Citation | Panaro BL, et al. (2020) Intestine-selective reduction of Gcg expression reveals the importance of the distal gut for GLP-1 secretion. Mol Metab 37:100990 |
| abstractText | OBJECTIVE: Glucagon-like peptide-1 is a nutrient-sensitive hormone secreted from enteroendocrine L cells within the small and large bowel. Although GLP-1 levels rise rapidly in response to food ingestion, the greatest density of L cells is localized to the distal small bowel and colon. Here, we assessed the importance of the distal gut in the acute L cell response to diverse secretagogues. METHODS: Circulating levels of glucose and plasma GLP-1 were measured in response to the administration of L cell secretagogues in wild-type mice and in mice with (1) genetic reduction of Gcg expression throughout the small bowel and large bowel (Gcg(Gut-/-)) and (2) selective reduction of Gcg expression in the distal gut (Gcg(DistalGut-/-)). RESULTS: The acute GLP-1 response to olive oil or arginine administration was markedly diminished in Gcg(Gut-/-) but preserved in Gcg(DistalGut-/-) mice. In contrast, the increase in plasma GLP-1 levels following the administration of the GPR119 agonist AR231453, or the melanocortin-4 receptor (MC4R) agonist LY2112688, was markedly diminished in the Gcg(DistalGut-/-) mice. The GLP-1 response to LPS was also markedly attenuated in the Gcg(Gut-/-) mice and remained submaximal in the Gcg(DistalGut-/-) mice. Doses of metformin sufficient to lower glucose and increase GLP-1 levels in the Gcg(Gut+/+) mice retained their glucoregulatory activity, yet they failed to increase GLP-1 levels in the Gcg(Gut-/-) mice. Surprisingly, the actions of metformin to increase plasma GLP-1 levels were substantially attenuated in the Gcg(DistalGut-/-) mice. CONCLUSION: These findings further establish the importance of the proximal gut for the acute response to nutrient-related GLP-1 secretagogues. In contrast, we identify essential contributions of the distal gut to (i) the rapid induction of circulating GLP-1 levels in response to pharmacological selective agonism of G-protein-coupled receptors, (ii) the increased GLP-1 levels following the activation of Toll-Like Receptors with LPS, and iii) the acute GLP-1 response to metformin. Collectively, these results reveal that distal gut Gcg + endocrine cells are rapid responders to structurally and functionally diverse GLP-1 secretagogues. |
