title: Thyroid transcription factor-1 regulates feeding behavior via melanocortin pathway in the hypothalamus.
abstract: OBJECTIVE
  α-Melanocyte-stimulating hormone (α-MSH) and agouti-related peptide (AgRP) control energy homeostasis by their opposing actions on melanocortin receptors (MC3/4R) in the hypothalamus. We previously reported that thyroid transcription factor-1 (TTF-1) controls feeding behavior in the hypothalamus. This study aims to identify the function of TTF-1 in the transcriptional regulation of AgRP and α-MSH synthesis for the control of feeding behavior.
  
  
  METHODS
  TTF-1 activity in AgRP and pro-opiomelanocortin (POMC) transcription was examined using gel-shift and promoter assays and an in vivo model of TTF-1 synthesis inhibition by intracerebroventricular injection of an antisense (AS) oligodeoxynucleotide (ODN). Double immunohistochemistry was performed to colocalize TTF-1 and AgRP or α-MSH in the hypothalamic arcuate nucleus (ARC). To determine whether TTF-1 action on food intake is mediated through MC3/4R, we measured changes in food intake upon intracerebroventricular injection of MC3/4R antagonists (SHU9119 and AgRP) into rat brain preinjected with the AS ODN.
  
  
  RESULTS
  TTF-1 stimulated AgRP but inhibited POMC transcription by binding to the promoters of these genes. TTF-1 was widely distributed in the hypothalamus, but we identified some cells coexpressing TTF-1 and AgRP or α-MSH in the ARC. In addition, intracerebroventricular administration of leptin decreased TTF-1 expression in the hypothalamus, and AS ODN-induced inhibition of TTF-1 expression decreased food intake and AgRP expression but increased α-MSH expression. Anorexia induced by the AS ODN was attenuated by the administration of MC3/4R antagonists.
  
  
  CONCLUSIONS
  TTF-1 transcriptionally regulates synthesis of AgRP and α-MSH in the ARC and affects feeding behavior via the melanocortin pathway.
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, University of Ulsan, Ulsan, South Korea.
authors.forename: Jae Geun
authors.initials: JG
authors.lastname: Kim
authors.forename: Byong Seo
authors.initials: BS
authors.lastname: Park
authors.forename: Chang Ho
authors.initials: CH
authors.lastname: Yun
authors.forename: Hyun Jun
authors.initials: HJ
authors.lastname: Kim
authors.forename: Sang Soo
authors.initials: SS
authors.lastname: Kang
authors.forename: Angela Valentina
authors.initials: AV
authors.lastname: D'Elia
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Damante
authors.forename: Ki-Up
authors.initials: KU
authors.lastname: Lee
authors.forename: Jeong Woo
authors.initials: JW
authors.lastname: Park
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Kim
authors.forename: Il Seong
authors.initials: IS
authors.lastname: Namgoong
authors.forename: Young Il
authors.initials: YI
authors.lastname: Kim
authors.forename: Byung Ju
authors.initials: BJ
authors.lastname: Lee
mesh_terms: D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D004435:Eating / Q000187:drug effects / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000521:alpha-MSH / Q000235:genetics / Q000378:metabolism*
chemical_list: D054369:Agouti-Related Protein; C000614414:Nkx2-1 protein, mouse; C000614416:Nkx2-1 protein, rat; D009687:Nuclear Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; C103272:SHU 9119; D000521:alpha-MSH; D009074:Melanocyte-Stimulating Hormones