title: Ghrelin stimulates corticotropin-releasing factor and vasopressin gene expression in rat hypothalamic 4B cells.
abstract: Corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) play a central role in regulating the stress response. In response to stress, CRF and AVP neurons in the hypothalamic paraventricular nucleus secrete the peptides to stimulate the release of adrenocorticotropic hormone from the anterior pituitary. Ghrelin, an endogenous ligand of the growth hormone-releasing peptide receptors (GHSR), has been shown to stimulate the release of CRF and AVP by rat hypothalamic explants. However, little is known about the ability of the ghrelin signaling pathways to activate the CRF and AVP genes in the hypothalamus. In the present study, we examined the direct effect of ghrelin on CRF and AVP gene expression in hypothalamic 4B cells, which show the characteristics of the hypothalamic parvocellular paraventricular nucleus neurons. Cells were transfected with CRF or AVP promoter to examine the activity of each promoter. Ghrelin stimulated the promoter activities and mRNA levels for both CRF and AVP. The involvement of a protein kinase pathway was examined using inhibitors. Protein kinase A and phospholipase C pathways were shown to be involved in ghrelin-induced increases in both CRF and AVP promoter activities. GHSR type 1a (GHSR1a) mRNA levels were also increased by ghrelin, and these ghrelin-induced levels were suppressed by a GHSR1a antagonist. Thus, ghrelin-dependent pathways are involved in the regulation of CRF and AVP gene expression in the hypothalamus: ghrelin, an orexigenic hormone, stimulates CRF, an anorexigenic/anxiogenic factor in the hypothalamus, resulting in hypothalamic-pituitary-adrenal axis activation to stimulate the release of glucocorticoids.
authors: Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, Japan. kkageyama@hkg.odn.ne.jp
authors: Kazunori
authors: K
authors: Kageyama
authors: Yukiko
authors: Y
authors: Kumata
authors: Kanako
authors: K
authors: Akimoto
authors: Shinobu
authors: S
authors: Takayasu
authors: Naoki
authors: N
authors: Tamasawa
authors: Toshihiro
authors: T
authors: Suda
mesh_terms: D000818:Animals; D001127:Arginine Vasopressin / Q000096:biosynthesis*; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000096:biosynthesis*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D054439:Ghrelin / Q000494:pharmacology*; D007031:Hypothalamus / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D054439:Ghrelin; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D001127:Arginine Vasopressin; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D010738:Type C Phospholipases; D006152:Cyclic GMP