title: Glucagon-like peptide-1 receptor agonist, exendin-4, regulates feeding-associated neuropeptides in hypothalamic neurons in vivo and in vitro.
abstract: Exendin-4, a long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist, is a potential regulator of feeding behavior through its ability to inhibit gastric emptying, reduce food intake, and induce satiety. GLP-1R activation by exendin-4 induces anorexia; however, the specific populations of neuropeptidergic neurons activated by exendin-4 within the hypothalamus, the central regulator of energy homeostasis, remain unclear. This study determines whether exendin-4 regulates hypothalamic neuropeptide expression and explores the signaling mechanisms involved. The distribution and quantity of exendin-4-induced c-Fos immunoreactivity were evaluated to determine activation of α-melanocyte-stimulating hormone/proopiomelanocortin, neuropeptide Y, neurotensin (NT), and ghrelin neurons in hypothalamic nuclei during exendin-4-induced anorexia in mice. Additionally, exendin-4 action on NT and ghrelin transcript regulation was examined in immortalized hypothalamic neurons. With anorexia induced by intracerebroventricular exendin-4, α-melanocyte-stimulating hormone/proopiomelanocortin and neuropeptide Y neurons were activated in the arcuate nucleus, with simultaneous activation of NT-expressing neurons in the paraventricular nucleus, and ghrelin-expressing neurons in the arcuate nucleus, paraventricular nucleus, and periventricular hypothalamus, suggesting that neurons in one or more of these areas mediate the anorexic action of exendin-4. In the hypothalamic neuronal cell models, exendin-4 increased cAMP, cAMP response element-binding protein/activating transcription factor-1 and c-Fos activation, and via a protein kinase A-dependent mechanism regulated NT and ghrelin mRNA expression, indicating that these neuropeptides may serve as downstream mediators of exendin-4 action. These findings provide a previously unrecognized link between central GLP-1R activation by exendin-4 and the regulation of hypothalamic NT and ghrelin. Further understanding of this central GLP-1R activation may lead to safe and effective therapeutics for the treatment of metabolic disorders.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Prasad S
authors.initials: PS
authors.lastname: Dalvi
authors.forename: Anaies
authors.initials: A
authors.lastname: Nazarians-Armavil
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Purser
authors.forename: Denise D
authors.initials: DD
authors.lastname: Belsham
mesh_terms: D000818:Animals; D004435:Eating / Q000187:drug effects / Q000502:physiology; D000077270:Exenatide; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D054439:Ghrelin / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009478:Neuropeptide Y / Q000378:metabolism; D009496:Neurotensin / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D018027:Receptors, Glucagon / Q000819:agonists*; D014688:Venoms / Q000494:pharmacology*; D000521:alpha-MSH / Q000378:metabolism
chemical_list: D054439:Ghrelin; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D009478:Neuropeptide Y; D010455:Peptides; D016760:Proto-Oncogene Proteins c-fos; D018027:Receptors, Glucagon; D014688:Venoms; D009496:Neurotensin; D000521:alpha-MSH; D011333:Pro-Opiomelanocortin; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide