title: Brain-specific homeobox factor as a target selector for glucocorticoid receptor in energy balance.
abstract: The molecular basis underlying the physiologically well-defined orexigenic function of glucocorticoid (Gc) is unclear. Brain-specific homeobox factor (Bsx) is a positive regulator of the orexigenic neuropeptide, agouti-related peptide (AgRP), in AgRP neurons of the hypothalamic arcuate nucleus. Here, we show that in response to fasting-elevated Gc levels, Gc receptor (GR) and Bsx synergize to direct activation of AgRP transcription. This synergy is dictated by unique sequence features in a novel Gc response element in AgRP (AgRP-GRE). In contrast to AgRP-GRE, Bsx suppresses transactivation directed by many conventional GREs, functioning as a gene context-dependent modulator of GR actions or a target selector for GR. Consistent with this finding, AgRP-GRE drives fasting-dependent activation of a target gene specifically in GR(+) Bsx(+) AgRP neurons. These results define AgRP as a common orexigenic target gene of GR and Bsx and provide an opportunity to identify their additional common targets, facilitating our understanding of the molecular basis underlying the orexigenic activity of Gc and Bsx.
authors.affiliation: Neuroscience Section, Papé Family Pediatric Research Institute, Department of Pediatrics.
authors.forename: Bora
authors.initials: B
authors.lastname: Lee
authors.forename: Sun-Gyun
authors.initials: SG
authors.lastname: Kim
authors.forename: Juhee
authors.initials: J
authors.lastname: Kim
authors.forename: Kwan Yong
authors.initials: KY
authors.lastname: Choi
authors.forename: Seunghee
authors.initials: S
authors.lastname: Lee
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Lee
authors.forename: Jae W
authors.initials: JW
authors.lastname: Lee
mesh_terms: D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D017124:Conserved Sequence; D003907:Dexamethasone / Q000494:pharmacology; D004734:Energy Metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005938:Glucocorticoids / Q000494:pharmacology / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D018398:Homeodomain Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction
chemical_list: D054369:Agouti-Related Protein; C492588:Bsx protein, mouse; D005938:Glucocorticoids; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009478:Neuropeptide Y; D011965:Receptors, Glucocorticoid; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D003907:Dexamethasone