Neurotensin Is Co-Expressed, Co-Released And Acts Together With Glp-1 And Pyy In Enteroendocrine Control Of Metabolism

The two gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are well known to be co-expressed, co-stored and released together to co-act in the control of key metabolic target organs. However, recently it became clear that several other gut hormones can be co-expressed in the intestinal specific lineage of enteroendocrine cells. Here we focus on the anatomical and functional consequences of the co-expression of neurotensin with GLP-1 and PYY in the distal small intestine. FACS analysis, laser capture and triple staining demonstrated that GLP-1 cells in the crypts become increasingly multi-hormonal, i.e. co-expressing PYY and neurotensin as they move up the villus. Pro-glucagon promoter and pertussis toxin receptor driven cell ablation and reappearance studies indicated that although all the cells die, the GLP-1 cells reappear more quickly than PYY and neurotensin positive cells. High-resolution confocal fluorescence microscopy demonstrated that neurotensin is stored in secretory granules distinct from GLP-1 and PYY storing granules. Nevertheless, the three peptides were co-secreted from both perfused small intestines and colonic crypt cultures in response to a series of metabolite, neuropeptide and hormonal stimuli. Importantly, neurotensin acts synergistically i.e. more than additively together with GLP-1 and PYY to decrease palatable food intake and inhibit gastric emptying, but affects glucose homeostasis in a more complex manner. Thus, neurotensin is a major gut hormone deeply integrated with GLP-1 and PYY, which should be taken into account when exploiting the enteroendocrine regulation of metabolism pharmacologically.