Limits...
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.

Show MeSH
Schematic diagram showing the intramural sites of action of endogenous PYY and NPY in normal mouse and human colon mucosa. Direct activation of epithelial Y1 receptors by PYY (and NPY) will inhibit epithelial anion (Cl−) secretion. NPY released from submucosal secretomotor neurons can auto-inhibit its release (lefthand side, a Y2-mediated effect) and also, when released from interneurons, can inhibit (again via Y2 receptors) secretomotor (e.g., VIP-ergic) neurons. Endocrine PYY can co-activate neuronal Y2 receptors and predominant epithelial Y1 receptors, and both mechanisms result in sustained inhibition of epithelial Cl− secretion. The NANC neurotransmitter in the final secretomotor neuron (righthand side) has yet to be positively identified but is likely to be VIP, which in turn stimulates prolonged epithelial cyclic adenosine monophosphate–dependent Cl− secretion that can be inhibited by Y1 (or Y4) receptor activation. NPY, neuropeptide Y; PYY, peptide YY; VIP, vasoactive intestinal polypeptide.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2572019&req=5

fig3: Schematic diagram showing the intramural sites of action of endogenous PYY and NPY in normal mouse and human colon mucosa. Direct activation of epithelial Y1 receptors by PYY (and NPY) will inhibit epithelial anion (Cl−) secretion. NPY released from submucosal secretomotor neurons can auto-inhibit its release (lefthand side, a Y2-mediated effect) and also, when released from interneurons, can inhibit (again via Y2 receptors) secretomotor (e.g., VIP-ergic) neurons. Endocrine PYY can co-activate neuronal Y2 receptors and predominant epithelial Y1 receptors, and both mechanisms result in sustained inhibition of epithelial Cl− secretion. The NANC neurotransmitter in the final secretomotor neuron (righthand side) has yet to be positively identified but is likely to be VIP, which in turn stimulates prolonged epithelial cyclic adenosine monophosphate–dependent Cl− secretion that can be inhibited by Y1 (or Y4) receptor activation. NPY, neuropeptide Y; PYY, peptide YY; VIP, vasoactive intestinal polypeptide.

Mentions: Knockout of individual peptides revealed clear differences in functional losses in the absence of any changes in peptide distribution. The NPY−/− colon exhibited normal levels of Y1 tone that were not significantly altered by neuronal blockade, indicating a direct epithelial mechanism of PYY action (Fig. 2A,B). This agrees with previous studies of antisecretory responses activated by exogenous analogs [5,6] (Cox et al., unpublished observations). PYY ablation conversely reduced Y1 tone by ∼90% (Fig. 2C), whereas Y2 tone was partially inhibited (Fig. 2D) and the remaining residual responses were abolished by TTX and by inference must be NPY mediated. As predicted, double knockouts lacked Y1 and Y2 tonic absorption (Fig. 2A,B). We conclude that a combination of the two peptides are responsible for Y2 tonic absorption and that neuronal and epithelial mechanisms underpin this tonic effect, as indicated by the neurotoxin TTX's ability to partially inhibit antagonist responses in NPY−/− (Fig. 2B) and abolish remaining Y2 tone in the PYY−/− colon (Fig. 2D). In contrast, NPY has a minor role as a mediator of Y1 tone (Fig. 2C). The location of Y1 receptors in basolateral poles of epithelia surrounding PYY-positive endocrine cells in human colon [26] fits well with the functional PYY–Y1 interactions observed in this tissue and in mouse colon (as shown in Fig. 3). In these tissues we have no evidence for submucous plexus or mucosal neuron Y1 expression and this agrees with the more limited distribution of Y1-receptor immunoreactivity noted by Matsuda et al. [27]. They observed only Y1 labeling of myenteric nerves (removed with smooth muscle from our preparations), a few endocrine-like cells, and specific larger blood vessels.


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

Cox HM - Nutrition (2008)

Schematic diagram showing the intramural sites of action of endogenous PYY and NPY in normal mouse and human colon mucosa. Direct activation of epithelial Y1 receptors by PYY (and NPY) will inhibit epithelial anion (Cl−) secretion. NPY released from submucosal secretomotor neurons can auto-inhibit its release (lefthand side, a Y2-mediated effect) and also, when released from interneurons, can inhibit (again via Y2 receptors) secretomotor (e.g., VIP-ergic) neurons. Endocrine PYY can co-activate neuronal Y2 receptors and predominant epithelial Y1 receptors, and both mechanisms result in sustained inhibition of epithelial Cl− secretion. The NANC neurotransmitter in the final secretomotor neuron (righthand side) has yet to be positively identified but is likely to be VIP, which in turn stimulates prolonged epithelial cyclic adenosine monophosphate–dependent Cl− secretion that can be inhibited by Y1 (or Y4) receptor activation. NPY, neuropeptide Y; PYY, peptide YY; VIP, vasoactive intestinal polypeptide.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Schematic diagram showing the intramural sites of action of endogenous PYY and NPY in normal mouse and human colon mucosa. Direct activation of epithelial Y1 receptors by PYY (and NPY) will inhibit epithelial anion (Cl−) secretion. NPY released from submucosal secretomotor neurons can auto-inhibit its release (lefthand side, a Y2-mediated effect) and also, when released from interneurons, can inhibit (again via Y2 receptors) secretomotor (e.g., VIP-ergic) neurons. Endocrine PYY can co-activate neuronal Y2 receptors and predominant epithelial Y1 receptors, and both mechanisms result in sustained inhibition of epithelial Cl− secretion. The NANC neurotransmitter in the final secretomotor neuron (righthand side) has yet to be positively identified but is likely to be VIP, which in turn stimulates prolonged epithelial cyclic adenosine monophosphate–dependent Cl− secretion that can be inhibited by Y1 (or Y4) receptor activation. NPY, neuropeptide Y; PYY, peptide YY; VIP, vasoactive intestinal polypeptide.
Mentions: Knockout of individual peptides revealed clear differences in functional losses in the absence of any changes in peptide distribution. The NPY−/− colon exhibited normal levels of Y1 tone that were not significantly altered by neuronal blockade, indicating a direct epithelial mechanism of PYY action (Fig. 2A,B). This agrees with previous studies of antisecretory responses activated by exogenous analogs [5,6] (Cox et al., unpublished observations). PYY ablation conversely reduced Y1 tone by ∼90% (Fig. 2C), whereas Y2 tone was partially inhibited (Fig. 2D) and the remaining residual responses were abolished by TTX and by inference must be NPY mediated. As predicted, double knockouts lacked Y1 and Y2 tonic absorption (Fig. 2A,B). We conclude that a combination of the two peptides are responsible for Y2 tonic absorption and that neuronal and epithelial mechanisms underpin this tonic effect, as indicated by the neurotoxin TTX's ability to partially inhibit antagonist responses in NPY−/− (Fig. 2B) and abolish remaining Y2 tone in the PYY−/− colon (Fig. 2D). In contrast, NPY has a minor role as a mediator of Y1 tone (Fig. 2C). The location of Y1 receptors in basolateral poles of epithelia surrounding PYY-positive endocrine cells in human colon [26] fits well with the functional PYY–Y1 interactions observed in this tissue and in mouse colon (as shown in Fig. 3). In these tissues we have no evidence for submucous plexus or mucosal neuron Y1 expression and this agrees with the more limited distribution of Y1-receptor immunoreactivity noted by Matsuda et al. [27]. They observed only Y1 labeling of myenteric nerves (removed with smooth muscle from our preparations), a few endocrine-like cells, and specific larger blood vessels.

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