1,25-Dihydroxyvitamin D regulates expression of the tryptophan hydroxylase 2 and leptin genes

implication for behavioral influences of vitamin D

Ichiro Kaneko, Marya S. Sabir, Christopher M. Dussik, G. Kerr Whitfield, Amitis Karrys, Jui Cheng Hsieh, Mark R. Haussler, Mark B. Meyer, J. Wesley Pike, Peter Jurutka

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

To investigate vitamin D-related control of brain-expressed genes, candidate vitamin D responsive elements (VDREs) at -7/-10 kb in human tryptophan hydroxylase (TPH)2 were probed. Both VDREs bound the vitamin D receptor (VDR)-retinoid X receptor (RXR) complex and drove reporter gene transcription in response to 1,25-dihydroxyvitamin D3 (1,25D). Brain TPH2 mRNA, encoding the rate-limiting enzyme in serotonin synthesis, was induced 2.2-fold by 10 nM 1,25D in human U87 glioblastoma cells and 47.8-fold in rat serotonergic RN46A-B14 cells. 1,25D regulation of leptin (Lep), encoding a serotoninlike satiety factor, was also examined. In mouse adipocytes, 1,25D repressed leptin mRNA levels by at least 84%, whereas 1,25D induced leptin mRNA 15.1-fold in human glioblastoma cells. Chromatin immunoprecipitation sequencing analysis of the mouse Lep gene in response to 1,25D revealed a cluster of regulatory sites (cis-regulatory module; CRM) at -28 kb that 1,25D-dependently docked VDR, RXR, C/EBPβ, and RUNX2. This CRM harbored 3 VDREs and single C/EBPβ and RUNX2 sites. Therefore, the expression of human TPH2 and mouse Lep are governed by 1,25D, potentially via respective VDREs located at -7/-10 kb and -28 kb. These results imply that vitamin D affects brain serotonin concentrations, which may be relevant to psychiatric disorders, such as autism, and may control leptin levels and affect eating behavior.

Original languageEnglish (US)
Pages (from-to)4023-4035
Number of pages13
JournalThe FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume29
Issue number9
DOIs
StatePublished - Sep 1 2015

Fingerprint

Tryptophan Hydroxylase
Calcitriol
Leptin
Vitamin D
Genes
Retinoid X Receptors
Brain
Calcitriol Receptors
Glioblastoma
Messenger RNA
Serotonin
1,25-dihydroxyvitamin D
Cholecalciferol
Chromatin Immunoprecipitation
Level control
Feeding Behavior
Transcription
Autistic Disorder
Reporter Genes
Adipocytes

Keywords

  • chromatin immunoprecipitation
  • cis-regulatory module
  • CNS
  • neuropsychiatric disorders
  • serotonin

ASJC Scopus subject areas

  • Medicine(all)

Cite this

1,25-Dihydroxyvitamin D regulates expression of the tryptophan hydroxylase 2 and leptin genes : implication for behavioral influences of vitamin D. / Kaneko, Ichiro; Sabir, Marya S.; Dussik, Christopher M.; Whitfield, G. Kerr; Karrys, Amitis; Hsieh, Jui Cheng; Haussler, Mark R.; Meyer, Mark B.; Pike, J. Wesley; Jurutka, Peter.

In: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Vol. 29, No. 9, 01.09.2015, p. 4023-4035.

Research output: Contribution to journalArticle

Kaneko, Ichiro ; Sabir, Marya S. ; Dussik, Christopher M. ; Whitfield, G. Kerr ; Karrys, Amitis ; Hsieh, Jui Cheng ; Haussler, Mark R. ; Meyer, Mark B. ; Pike, J. Wesley ; Jurutka, Peter. / 1,25-Dihydroxyvitamin D regulates expression of the tryptophan hydroxylase 2 and leptin genes : implication for behavioral influences of vitamin D. In: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2015 ; Vol. 29, No. 9. pp. 4023-4035.
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