Neuroendocrine peptide mechanisms controlling intestinal epithelial function

• Dietary nutrients and microbial metabolites can selectively activate different EECs.
• L cell peptides, PYY and GLP-1 can be stored independently and released differentially.
• Selective GPR119, FFA1-4 and MC4R agonism cause L cell peptide release but, there are some notable species and intestinal area differences.
• Dual agonism amplifies incretin release and could be more physiologically relevant.

Enteroendocrine cells (EECs) contain different combinations of hormones, which are released following stimulation of nutrient receptors that are selectively expressed by these cells. This chemosensation varies according to the intestinal area and species of interest, and responses to meals are rapidly modified following bariatric surgery. Such surgically-induced gastrointestinal (GI) changes highlight considerable enteroplasticity, however our understanding of even the acute physiological control and consequences of neuroendocrine peptide release is still under-developed. This review focuses on recent advances in nutrient G protein-coupled receptor (GPCR)-chemosensation in L cells, the patterns of peptide release and consequent changes in GI function. A clearer resolution of these mucosal mechanisms will shed light on potential receptor-target combinations that could provide less-invasive anti-diabesity strategies in future.