Endogenous PYY and NPY mediate tonic Y(1)- and Y(2)-mediated absorption in human and mouse colon

OBJECTIVE: To establish the functional significance of endogenous peptide YY (PYY) and neuropeptide Y (NPY) as mediators of Y(1) and Y(2) absorptive tone in colonic mucosa. METHODS: Functional studies utilized descending colon from adult mice (wild type [WT] and peptide nulls) and ex vivo human colonic tissue (from patients undergoing bowel resections) measuring changes in basal ion transport. Peak increases in ion transport to Y(1) or Y(2) antagonists (BIBO3304 300 nM; BIIE0246 1 μM) were pooled (mean ± SEM) and compared using Student's unpaired t test (P ≤ 0.05); some tissues received tetrodotoxin (TTX; 100 nM). PYY-positive L-cell numbers and NPY innervation were also compared. RESULTS: Y(1) and Y(2) tones were present in human and WT mouse colon mucosa and only the latter was TTX sensitive. Y(1) tone was unchanged in NPY(−/−) but was ∼90% inhibited in PYY(−/−) and abolished in PYYNPY(−/−) colon mucosa. Y(2) tone was reduced ∼50% in NPY(−/−) and PYY(−/−) tissues and was absent from PYYNPY(−/−) colon. Residual Y(2) and Y(1) tones present in PYY(−/−) mucosa were abolished by TTX. PYY ablation had no apparent effect on NPY innervation and PYY-positive cells were observed at the same frequency in NPY(−/−) (56.7 ± 6.8 cells/section) and WT (55.0 ± 4.6 cells/section) colons. Double knockouts lacked PYY and NPY expression, but endocrine cells and enteric nerves were present with similar frequencies to those of WT mice. CONCLUSION: Endogenous PYY mediates Y(1) absorptive tone that is epithelial in origin, whereas Y(2) tone is a combination of PYY and NPY mediation.