Peptide YY is critical for acylethanolamine receptor Gpr119-induced activation of gastrointestinal mucosal responses.
Peptide YY (PYY) is released following food intake and regulates intestinal function and glucose homeostasis, but the mechanisms underpinning these processes are unclear. Enteroendocrine L cells contain PYY and express the acylethanolamine receptor, Gpr119. Here, we show that Gpr119 activation inhibited epithelial electrolyte secretion in human and mouse colon in a glucose-sensitive manner. Endogenous PYY selectively mediated these effects, since PYY(-/-) mice showed no Gpr119 response, but responses were observed in NPY(-/-) mice. Importantly, Gpr119 responses in wild-type (WT) mouse tissue and human colon were abolished by Y(1) receptor antagonism, but were not enhanced by dipeptidylpeptidase IV blockade, indicating that PYY processing to PYY(3-36) was not important. In addition, Gpr119 agonism reduced glycemic excursions after oral glucose delivery to WT mice but not PYY(-/-) mice. Taken together, these data demonstrate a previously unrecognized role of PYY in mediating intestinal Gpr119 activity and an associated function in controlling glucose tolerance.
King's College London, Wolfson Centre for Age-Related Diseases, Guy's Campus, London SE1 1UL, UK. helen.cox@kcl.ac.uk
Helen M
HM
Cox
Iain R
IR
Tough
Anne-Marie
AM
Woolston
Lei
L
Zhang
Amy D
AD
Nguyen
Amanda
A
Sainsbury
Herbert
H
Herzog
D000147:Acids, Heterocyclic / Q000494:pharmacology; D000818:Animals; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D004573:Electrolytes / Q000378:metabolism; D019858:Enteroendocrine Cells / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010069:Oxadiazoles / Q000494:pharmacology; D019894:Peptide YY / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors / Q000378:metabolism
D000147:Acids, Heterocyclic; D004573:Electrolytes; C519854:GPR119 protein, human; C516207:Gpr119 protein, mouse; D010069:Oxadiazoles; C534146:PSN 632408; D043562:Receptors, G-Protein-Coupled; D017476:Receptors, Neuropeptide Y; D019894:Peptide YY; D052216:Glucagon-Like Peptide 1; D005947:Glucose