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Endogenous PYY and NPY mediate tonic Y1- and Y2-mediated absorption in human and mouse colon.

Cox HM - Nutrition (2008)

Bottom Line: PYY-positive L-cell numbers and NPY innervation were also compared.Y(2) tone was reduced approximately 50% in NPY(-/-) and PYY(-/-) tissues and was absent from PYYNPY(-/-) colon.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.

View Article: PubMed Central - PubMed

Affiliation: King's College London, Wolfson Centre for Age-Related Diseases, Guy's Campus, London, United Kingdom. helen.cox@kcl.ac.uk

ABSTRACT

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 s) 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 microM) were pooled (mean +/- SEM) and compared using Student's unpaired t test (P

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 approximately 90% inhibited in PYY(-/-) and abolished in PYYNPY(-/-) colon mucosa. Y(2) tone was reduced approximately 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.

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Y1 (3304) and Y2 (0246) antagonists reveal absorptive tone but 3435 (an inactive Y1 isomer) was ineffective. Y1 and Y2 antagonism raised Isc in human (A, B) and wild-type (C, D) mouse colon mucosa, respectively. Y1 tone in both tissues was insensitive to TTX (+TTX, 100 nM; A, C), whereas Y2 tone was significantly reduced by TTX pretreatment of both mucosae (B, D). Asterisks indicate statistical differences between control and experimental data groups (*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001) and bars represent mean ± SEM from 3–10 observations. ΔIsc, change in short-circuit current; TTX, tetrodotoxin; 0246, BIIE0246; 3304, BIBO3304; 3435, BIBP3435.
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fig1: Y1 (3304) and Y2 (0246) antagonists reveal absorptive tone but 3435 (an inactive Y1 isomer) was ineffective. Y1 and Y2 antagonism raised Isc in human (A, B) and wild-type (C, D) mouse colon mucosa, respectively. Y1 tone in both tissues was insensitive to TTX (+TTX, 100 nM; A, C), whereas Y2 tone was significantly reduced by TTX pretreatment of both mucosae (B, D). Asterisks indicate statistical differences between control and experimental data groups (*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001) and bars represent mean ± SEM from 3–10 observations. ΔIsc, change in short-circuit current; TTX, tetrodotoxin; 0246, BIIE0246; 3304, BIBO3304; 3435, BIBP3435.

Mentions: Table 1 presents the basal resistances and Isc levels for human and murine colon mucosae. Values were similar to those published previously for human and WT mouse mucosae [5,6] and basal levels of Isc and TTX-sensitive Isc in NPY−/− colon specifically were significantly higher than those of WT tissue. The competitive Y1 antagonist, BIBO3304, caused sustained elevations in Isc that were maximal at 15 min in WT mouse and human colon mucosa and neither of these effects was sensitive to TTX pretreatment (Fig. 1A,C). The inactive Y1 antagonist enantiomer, BIBP3435, had no effect per se (P ≤ 0.01 in both tissues). Blockade of Y2-mediated absorption (with Y2 antagonist BIIE0246) also increased basal Isc levels that were virtually abolished by the neurotoxin TTX (Fig. 1B,D). This indicates that Y2 tone is predominantly neuronal in contrast to Y1 absorptive tone that is non-neuronal in both colonic tissues.


Endogenous PYY and NPY mediate tonic Y1- and Y2-mediated absorption in human and mouse colon.

Cox HM - Nutrition (2008)

Y1 (3304) and Y2 (0246) antagonists reveal absorptive tone but 3435 (an inactive Y1 isomer) was ineffective. Y1 and Y2 antagonism raised Isc in human (A, B) and wild-type (C, D) mouse colon mucosa, respectively. Y1 tone in both tissues was insensitive to TTX (+TTX, 100 nM; A, C), whereas Y2 tone was significantly reduced by TTX pretreatment of both mucosae (B, D). Asterisks indicate statistical differences between control and experimental data groups (*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001) and bars represent mean ± SEM from 3–10 observations. ΔIsc, change in short-circuit current; TTX, tetrodotoxin; 0246, BIIE0246; 3304, BIBO3304; 3435, BIBP3435.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2572019&req=5

fig1: Y1 (3304) and Y2 (0246) antagonists reveal absorptive tone but 3435 (an inactive Y1 isomer) was ineffective. Y1 and Y2 antagonism raised Isc in human (A, B) and wild-type (C, D) mouse colon mucosa, respectively. Y1 tone in both tissues was insensitive to TTX (+TTX, 100 nM; A, C), whereas Y2 tone was significantly reduced by TTX pretreatment of both mucosae (B, D). Asterisks indicate statistical differences between control and experimental data groups (*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001) and bars represent mean ± SEM from 3–10 observations. ΔIsc, change in short-circuit current; TTX, tetrodotoxin; 0246, BIIE0246; 3304, BIBO3304; 3435, BIBP3435.
Mentions: Table 1 presents the basal resistances and Isc levels for human and murine colon mucosae. Values were similar to those published previously for human and WT mouse mucosae [5,6] and basal levels of Isc and TTX-sensitive Isc in NPY−/− colon specifically were significantly higher than those of WT tissue. The competitive Y1 antagonist, BIBO3304, caused sustained elevations in Isc that were maximal at 15 min in WT mouse and human colon mucosa and neither of these effects was sensitive to TTX pretreatment (Fig. 1A,C). The inactive Y1 antagonist enantiomer, BIBP3435, had no effect per se (P ≤ 0.01 in both tissues). Blockade of Y2-mediated absorption (with Y2 antagonist BIIE0246) also increased basal Isc levels that were virtually abolished by the neurotoxin TTX (Fig. 1B,D). This indicates that Y2 tone is predominantly neuronal in contrast to Y1 absorptive tone that is non-neuronal in both colonic tissues.

Bottom Line: PYY-positive L-cell numbers and NPY innervation were also compared.Y(2) tone was reduced approximately 50% in NPY(-/-) and PYY(-/-) tissues and was absent from PYYNPY(-/-) colon.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.

View Article: PubMed Central - PubMed

Affiliation: King's College London, Wolfson Centre for Age-Related Diseases, Guy's Campus, London, United Kingdom. helen.cox@kcl.ac.uk

ABSTRACT

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 s) 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 microM) were pooled (mean +/- SEM) and compared using Student's unpaired t test (P

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 approximately 90% inhibited in PYY(-/-) and abolished in PYYNPY(-/-) colon mucosa. Y(2) tone was reduced approximately 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.

Show MeSH
Related in: MedlinePlus