Peptide YY is critical for acylethanolamine receptor Gpr119-induced activation of gastrointestinal mucosal responses

Cell Metab. 2010 Jun 9;11(6):532-42. doi: 10.1016/j.cmet.2010.04.014.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acids, Heterocyclic / pharmacology
  • Animals
  • Colon / drug effects
  • Colon / metabolism
  • Electrolytes / metabolism
  • Enteroendocrine Cells / metabolism
  • Gastric Mucosa / metabolism*
  • Glucagon-Like Peptide 1 / metabolism
  • Glucose / metabolism
  • Humans
  • Mice
  • Mice, Knockout
  • Oxadiazoles / pharmacology
  • Peptide YY / genetics
  • Peptide YY / metabolism*
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Neuropeptide Y / antagonists & inhibitors
  • Receptors, Neuropeptide Y / metabolism


  • Acids, Heterocyclic
  • Electrolytes
  • GPR119 protein, human
  • Gpr119 protein, mouse
  • Oxadiazoles
  • PSN 632408
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide Y
  • Peptide YY
  • Glucagon-Like Peptide 1
  • Glucose