title: Peripheral α2-β1 adrenergic interactions mediate the ghrelin response to brain urocortin 1 in rats.
abstract: The autonomic nervous system (ANS) conveys neuronal input from the brain to the stomach. We investigated mechanisms through which urocortin 1 (UCN1) injected intracerebroventricularly (ICV, 300 pmol/rat) inhibits circulating ghrelin in rats. This was achieved by assessing (1) the induction of c-fos gene expression as a marker of neuronal activation in specific hypothalamic and caudal brainstem regulating ANS; (2) the influence of vagotomy and pharmacological blockade of central and peripheral α- and β-adrenergic receptor (AR) on ICV UCN1-induced reduction of plasma ghrelin levels (determined by ELISA); and (3) the relevance of this pathway in the feeding response to a fast in rats. UCN1 increased c-fos mRNA expression in key brain sites influencing sympathetic activity namely the hypothalamic paraventricular and ventromedial nuclei, locus coeruleus, nucleus of the solitary tract, and rostral ventrolateral medulla, by 16-, 29-, 6-, 37-, and 13-fold, respectively. In contrast, the dorsal motor nucleus of the vagus had little c-fos mRNA expression and ICV UCN1 induced a similar reduction in acylated ghrelin in the sham-operated (31%) and vagotomized (41%) rats. An intraperitoneal (IP) injection of either a non-selective α- or selective α2-AR antagonist reduced, while a selective α2-AR agonist enhanced ICV UCN1-induced suppression of plasma acylated ghrelin levels. In addition, IP injection of a non-selective β- or selective β1-AR agonist blocked, and selective β1-AR antagonist augmented, the ghrelin response to ICV UCN1. The IP injections of a selective α1- or non-selective β or β2-AR antagonists, or any of the pretreatments given ICV had no effect. ICV UCN1 reduced the 2-h food intake in response to a fast by 80%, and this effect was partially prevented by a selective α2-AR antagonist. These data suggest that ICV UCN1 reduces plasma ghrelin mainly through the brain sympathetic component of the ANS and peripheral AR specifically α2-AR activation and inactivation of β1-AR. The α2-AR pathway contributes to the associated reduction in food intake.
authors.affiliation: Department of Gastroenterology and Hepatology, Saitama Medical Center, Saitama Medical University, Saitama 3508550, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Yakabi
authors.affiliation: Department of Gastroenterology and Hepatology, Saitama Medical Center, Saitama Medical University, Saitama 3508550, Japan; Tsumura Research Laboratories, Tsumura & Co., Ibaraki 3001192, Japan. Electronic address: harada_yumi@mail.tsumura.co.jp.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Harada
authors.affiliation: Department of Gastroenterology and Hepatology, Saitama Medical Center, Saitama Medical University, Saitama 3508550, Japan; Department of Laboratory Sciences, Gunma University School of Health Sciences, Gunma 3718511, Japan.
authors.forename: Kiyoshige
authors.initials: K
authors.lastname: Takayama
authors.affiliation: Department of Gastroenterology and Hepatology, Saitama Medical Center, Saitama Medical University, Saitama 3508550, Japan; Central Research Laboratories, Teikyo University Chiba Medical Center, Chiba 2990111, Japan.
authors.forename: Shoki
authors.initials: S
authors.lastname: Ro
authors.affiliation: Department of Gastroenterology and Hepatology, Saitama Medical Center, Saitama Medical University, Saitama 3508550, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Ochiai
authors.affiliation: Tsumura Research Laboratories, Tsumura & Co., Ibaraki 3001192, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Iizuka
authors.affiliation: Tsumura Research Laboratories, Tsumura & Co., Ibaraki 3001192, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Hattori
authors.affiliation: CURE/Digestive Diseases Center and Center for Neurobiology of Stress, Department of Medicine, Digestive Diseases Division, University of California at Los Angeles, and VA Greater Los Angeles Health Care System, Los Angeles, CA 90078, USA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Wang
authors.affiliation: CURE/Digestive Diseases Center and Center for Neurobiology of Stress, Department of Medicine, Digestive Diseases Division, University of California at Los Angeles, and VA Greater Los Angeles Health Care System, Los Angeles, CA 90078, USA.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Taché
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004435:Eating / Q000187:drug effects*; D054439:Ghrelin / Q000097:blood*; D008297:Male; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D054832:Urocortins / Q000494:pharmacology*; D014628:Vagotomy
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D058671:Adrenergic beta-1 Receptor Antagonists; D054439:Ghrelin; D016760:Proto-Oncogene Proteins c-fos; D018341:Receptors, Adrenergic, alpha-2; D018342:Receptors, Adrenergic, beta-1; D054832:Urocortins
keywords: Acylated ghrelin; Adrenergic receptors; Food intake; Rikkunshito; Stress; Urocortin 1