Glucagon-like peptide (GLP)-2 action in the murine central nervous system is enhanced by elimination of GLP-1 receptor signaling.
Glucagon-like peptide-2 (GLP-2) regulates energy homeostasis via effects on nutrient absorption and maintenance of gut mucosal epithelial integrity. The biological actions of GLP-2 in the central nervous system (CNS) remain poorly understood. We studied the sites of endogenous GLP-2 receptor (GLP-2R) expression, the localization of transgenic LacZ expression under the control of the mouse GLP-2R promoter, and the actions of GLP-2 in the murine CNS. GLP-2R expression was detected in multiple extrahypothalamic regions of the mouse and rat CNS, including cell groups in the cerebellum, medulla, amygdala, hippocampus, dentate gyrus, pons, cerebral cortex, and pituitary. A 1.5-kilobase fragment of the mouse GLP-2R promoter directed LacZ expression to the gastrointestinal tract and CNS regions in the mouse that exhibited endogenous GLP-2R expression, including the cerebellum, amygdala, hippocampus, and dentate gyrus. Intracerebroventricular injection of GLP-2 significantly inhibited food intake during dark-phase feeding in wild-type mice. Disruption of glucagon-like peptide-1 receptor (GLP-1R) signaling with the antagonist exendin-(9-39) in wild-type mice or genetically in GLP-1R(-)/- mice significantly potentiated the anorectic actions of GLP-2. These findings illustrate that CNS GLP-2R expression is not restricted to hypothalamic nuclei and demonstrate that the anorectic effects of GLP-2 are transient and modulated by the presence or absence of GLP-1R signaling in vivo.
Department of Medicine, Banting and Best Diabetes Centre, Toronto General Hospital, Toronto, Ontario M5G 2C4, Canada.
J
J
Lovshin
J
J
Estall
B
B
Yusta
T J
TJ
Brown
D J
DJ
Drucker
D000595:Amino Acid Sequence; D000679:Amygdala / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology; D005768:Gastrointestinal Hormones / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1; D053767:Glucagon-Like Peptide 2; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009928:Organ Specificity; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D010902:Pituitary Gland / Q000187:drug effects / Q000502:physiology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D001616:beta-Galactosidase / Q000032:analysis / Q000235:genetics
C000593833:GLP1R protein, human; D005768:Gastrointestinal Hormones; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D053767:Glucagon-Like Peptide 2; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D012333:RNA, Messenger; D018027:Receptors, Glucagon; D011994:Recombinant Proteins; D052216:Glucagon-Like Peptide 1; D001616:beta-Galactosidase