title: Endogenous GLP-1 acts on paraventricular nucleus to suppress feeding: projection from nucleus tractus solitarius and activation of corticotropin-releasing hormone, nesfatin-1 and oxytocin neurons.
abstract: Glucagon-like peptide-1 (GLP-1) receptor agonists have been used to treat type 2 diabetic patients and shown to reduce food intake and body weight. The anorexigenic effects of GLP-1 and GLP-1 receptor agonists are thought to be mediated primarily via the hypothalamic paraventricular nucleus (PVN). GLP-1, an intestinal hormone, is also localized in the nucleus tractus solitarius (NTS) of the brain stem. However, the role of endogenous GLP-1, particularly that in the NTS neurons, in feeding regulation remains to be established. The present study examined whether the NTS GLP-1 neurons project to PVN and whether the endogenous GLP-1 acts on PVN to restrict feeding. Intra-PVN injection of GLP-1 receptor antagonist exendin (9-39) increased food intake. Injection of retrograde tracer into PVN combined with immunohistochemistry for GLP-1 in NTS revealed direct projection of NTS GLP-1 neurons to PVN. Moreover, GLP-1 evoked Ca(2+) signaling in single neurons isolated from PVN. The majority of GLP-1-responsive neurons were immunoreactive predominantly to corticotropin-releasing hormone (CRH) and nesfatin-1, and less frequently to oxytocin. These results indicate that endogenous GLP-1 targets PVN to restrict feeding behavior, in which the projection from NTS GLP-1 neurons and activation of CRH and nesfatin-1 neurons might be implicated. This study reveals a neuronal basis for the anorexigenic effect of endogenous GLP-1 in the brain.
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, 3311-1 Shimotsuke, Tochigi 329-0498, Japan; Division of Cardiovascular Medicine, Department of Internal Medicine, Jichi Medical University School of Medicine, 3311-1 Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Katsurada
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, 3311-1 Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Maejima
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, 3311-1 Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakata
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, 3311-1 Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Misato
authors.initials: M
authors.lastname: Kodaira
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, 3311-1 Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Shigetomo
authors.initials: S
authors.lastname: Suyama
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, 3311-1 Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Iwasaki
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Jichi Medical University School of Medicine, 3311-1 Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Kazuomi
authors.initials: K
authors.lastname: Kario
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, 3311-1 Shimotsuke, Tochigi 329-0498, Japan; Department of Development Physiology, Division of Adaptation Development, National Institute for Physiological Science, Okazaki, Aichi 444-8585, Japan. Electronic address: tyada@jichi.ac.jp.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yada
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000502:physiology*; D003346:Corticotropin-Releasing Hormone / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D004435:Eating / Q000187:drug effects / Q000502:physiology*; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000502:physiology*; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D008297:Male; D008845:Microinjections; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009434:Neural Pathways / Q000502:physiology; D009474:Neurons / Q000502:physiology; D000080866:Nucleobindins; D010121:Oxytocin / Q000502:physiology*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors; D017552:Solitary Nucleus / Q000502:physiology*
chemical_list: D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; C000630650:NUCB2 protein, human; D009419:Nerve Tissue Proteins; C000630652:Nucb1 protein, rat; D000080866:Nucleobindins; D010446:Peptide Fragments; D018027:Receptors, Glucagon; D010121:Oxytocin; C083773:exendin (9-39); D052216:Glucagon-Like Peptide 1; D003346:Corticotropin-Releasing Hormone
keywords: Corticotropin-releasing hormone; Feeding; Glucagon-like peptide-1; Nesfatin-1; Nucleus tractus solitarius; Paraventricular nucleus