1,25-Dihydroxyvitamin D regulates expression of the tryptophan hydroxylase 2 and leptin genes: implication for behavioral influences of vitamin D.

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.

• Authors: 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 W Jurutka
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 29 Issue 9 Pg. 4023-35 (Sep 2015) ISSN: 1530-6860 [Electronic] United States
• PMID: 26071405 (Publication Type: Journal Article)
• Copyright: © FASEB.

Chemical References

• Leptin
• RNA, Messenger
• TPH2 protein, human
• Tph2 protein, mouse
• Tryptophan Hydroxylase
• Calcitriol

Topics

• 3T3-L1 Cells
• Animals
• Autistic Disorder (metabolism)
• Behavior, Animal (drug effects)
• Calcitriol (pharmacology)
• Cell Line, Tumor
• Feeding Behavior (drug effects)
• Gene Expression Regulation (drug effects)
• HEK293 Cells
• Humans
• Leptin (biosynthesis)
• Mice
• RNA, Messenger (biosynthesis)
• Response Elements (drug effects)
• Tryptophan Hydroxylase (biosynthesis)