title: Glucagon-like peptide-1, corticotropin-releasing hormone, and hypothalamic neuronal histamine interact in the leptin-signaling pathway to regulate feeding behavior.
abstract: Glucagon-like peptide-1 (GLP-1), corticotropin-releasing hormone (CRH), and hypothalamic neuronal histamine suppress food intake, a target of leptin action in the brain. This study examined the interactions of GLP-1, CRH, and histamine downstream from the leptin-signaling pathway in regulating feeding behavior. Infusion of GLP-1 into the third cerebral ventricle (i3vt) at a dose of 1 mug significantly decreased the initial 1 h cumulative food intake in rats as compared with phosphate-buffered saline (PBS) controls. The GLP-1-induced suppression of feeding was partially attenuated by intraperitoneal pretreatment with alpha-fluoromethylhistidine (FMH), a specific suicide inhibitor of histidine decarboxylase, which depletes hypothalamic neuronal histamine. Pretreatment with alpha-helical CRH (10 microg/rat, i3vt), a nonselective CRH antagonist, abolished the GLP-1-induced suppression of feeding completely. I3vt infusion of GLP-1 increased the CRH content and histamine turnover assessed using the pargyline-induced accumulation of tele-methyl histamine (t-MH), a major metabolite of neuronal histamine, in the hypothalamus. The central infusion of CRH also induced the increase of histamine turnover and CRH receptor type 1 was localized on the cell body of histamine neuron. Pretreatment with exendin(9-39), a GLP-1 receptor antagonist, attenuated the leptin-induced increase in CRH content of the hypothalamus. Finally, i3vt infusion of leptin also increased histamine turnover in the hypothalamus. Pretreatment with exendin(9-39), alpha-helical CRH or both antagonists attenuated the leptin-induced responses of t-MH levels in the hypothalamus. These results suggest that CRH or hypothalamic neuronal histamine mediates the GLP-1-induced suppression of feeding behavior, that CRH mediates GLP-1 signaling to neuronal histamine and that a functional link from GLP-1 to neuronal histamine via CRH constitutes the leptin-signaling pathway regulating feeding behavior.
authors.affiliation: Department of Internal Medicine 1, Faculty of Medicine, Oita University, Hasama, Oita, Japan.
authors.forename: Koro
authors.initials: K
authors.lastname: Gotoh
authors.forename: Koji
authors.initials: K
authors.lastname: Fukagawa
authors.forename: Tomiyo
authors.initials: T
authors.lastname: Fukagawa
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Noguchi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kakuma
authors.forename: Toshiie
authors.initials: T
authors.lastname: Sakata
authors.forename: Hironobu
authors.initials: H
authors.lastname: Yoshimatsu
mesh_terms: D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D005247:Feeding Behavior / Q000187:drug effects*; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D006632:Histamine / Q000032:analysis / Q000502:physiology*; D007031:Hypothalamus / Q000502:physiology*; D007150:Immunohistochemistry; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D008761:Methylhistamines / Q000032:analysis; D008762:Methylhistidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D020738:Leptin; D008761:Methylhistamines; D008762:Methylhistidines; C028309:alpha-fluoromethylhistidine; D006632:Histamine; D052216:Glucagon-Like Peptide 1; D003346:Corticotropin-Releasing Hormone; C020404:tele-methylhistamine