title: Glucagon-like peptide-2 directly regulates hypothalamic neurons expressing neuropeptides linked to appetite control in vivo and in vitro.
abstract: Glucagon-like peptide-2 (GLP-2), a proglucagon-derived peptide, has been postulated to affect appetite at the level of the hypothalamus. To gain better insight into this process, a degradation-resistant GLP-2 analog, human (Gly(2))GLP-2(1-33) [h(Gly(2))GLP-2] was intracerebroventricularly injected into mice to examine its action on food and water intake and also activation of hypothalamic anorexigenic α-melanocyte-stimulating hormone/proopiomelanocortin, neurotensin, and orexigenic neuropeptide Y, and ghrelin neurons. Central h(Gly(2))GLP-2 administration significantly suppressed food and water intake with acute weight loss at 2 h. Further, central h(Gly(2))GLP-2 robustly induced c-Fos activation in the hypothalamic arcuate, dorsomedial, ventromedial, paraventricular, and the lateral hypothalamic nuclei. We found differential colocalization of neuropeptides with c-Fos in specific regions of the hypothalamus. To assess whether hypothalamic neuropeptides are directly regulated by GLP-2 in vitro, we used an adult-derived clonal, immortalized hypothalamic cell line, mHypoA-2/30, that endogenously expresses functional GLP-2 receptors (GLP-2R) and two of the feeding-related neuropeptides linked to GLP-2R activation in vivo: neurotensin and ghrelin. Treatment with h(Gly(2))GLP-2 stimulated c-Fos expression and phosphorylation of cAMP response element-binding protein/activating transcription factor-1. In addition, treatment with h(Gly(2))GLP-2 significantly increased neurotensin and ghrelin mRNA transcript levels by 50 and 95%, respectively, at 24 h after treatment in protein kinase A-dependent manner. Taken together, these findings implicate the protein kinase A pathway as the means by which GLP-2 can up-regulate hypothalamic neuropeptide mRNA levels and provide evidence for a link between central GLP-2R activation and specific hypothalamic neuropeptides involved in appetite regulation.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Prasad S
authors.initials: PS
authors.lastname: Dalvi
authors.forename: Denise D
authors.initials: DD
authors.lastname: Belsham
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects / Q000502:physiology; D004435:Eating / Q000187:drug effects* / Q000502:physiology; D054439:Ghrelin / Q000235:genetics / Q000378:metabolism; D053767:Glucagon-Like Peptide 2 / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008845:Microinjections; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D009496:Neurotensin / Q000235:genetics / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism
chemical_list: D054439:Ghrelin; D053767:Glucagon-Like Peptide 2; D009478:Neuropeptide Y; D016760:Proto-Oncogene Proteins c-fos; D009496:Neurotensin; D011333:Pro-Opiomelanocortin