title: Regulation of ghrelin signaling by a leptin-induced gene, negative regulatory element-binding protein, in the hypothalamic neurons.
abstract: Leptin, the product of the ob gene, plays important roles in the regulation of food intake and body weight through its receptor in the hypothalamus. To identify novel transcripts induced by leptin, we performed cDNA subtraction based on selective suppression of the polymerase chain reaction by using mRNA prepared from the forebrain of leptin-injected ob/ob mice. One of the genes isolated was a mouse homolog of human negative regulatory element-binding protein (NREBP). Its expression was markedly increased by leptin in the growth hormone secretagogue-receptor (GHS-R)-positive neurons of the arcuate nucleus and ventromedial hypothalamic nucleus. The promoter region of GHS-R contains one NREBP binding sequence, suggesting that NREBP regulates GHS-R transcription. Luciferase reporter assays showed that NREBP repressed GHS-R promoter activity in a hypothalamic neuronal cell line, GT1-7, and its repressive activity was abolished by the replacement of negative regulatory element in GHS-R promoter. Overexpression of NREBP reduced the protein expression of endogenous GHS-R without affecting the expression of ob-Rb in GT1-7 cells. To determine the functional importance of NREBP in the hypothalamus, we assessed the effects of NREBP on ghrelin action. Although phosphorylation of AMP-activated protein kinase α (AMPKα) was induced by ghrelin in GT1-7 cells, NREBP repressed ghrelin-induced AMPKα phosphorylation. These results suggest that leptin-induced NREBP is an important regulator of GHS-R expression in the hypothalamus and provides a novel molecular link between leptin and ghrelin signaling.
authors.affiliation: Department of Anatomy and Neurobiology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan.
authors.forename: Tadasuke
authors.initials: T
authors.lastname: Komori
authors.forename: Asako
authors.initials: A
authors.lastname: Doi
authors.forename: Hiroto
authors.initials: H
authors.lastname: Furuta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Wakao
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Nakao
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Nakazato
authors.forename: Kishio
authors.initials: K
authors.lastname: Nanjo
authors.forename: Emiko
authors.initials: E
authors.lastname: Senba
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Morikawa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D054439:Ghrelin / Q000235:genetics / Q000378:metabolism*; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism*; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D054440:Receptors, Ghrelin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D004268:DNA-Binding Proteins; D054439:Ghrelin; D020738:Leptin; D009687:Nuclear Proteins; D054440:Receptors, Ghrelin; C083666:Son protein, mouse