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 27/210 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 D 3 (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 228 kb that 1,25D-dependently docked VDR, RXR, C/EBPb, and RUNX2. This CRM harbored 3 VDREs and single C/EBPb and RUNX2 sites. Therefore, the expression of human TPH2 and mouse Lep are governed by 1,25D, potentially via respective VDREs located at 27/210 kb and 228 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.-Kaneko, I., Sabir, M. S., Dussik, C. M., Whitfield, G. K., Karrys, A., Hseih, J.-C., Haussler, M. R., Meyer, M. B., Pike, J. W., Jurutka, P. W. 1,25-dihydroxyvitamin D regulates expression of the tryptophan hydroxylase 2 and leptin genes: implication for behavioral influences of vitamin D. FASEB J. 29, 4023-4035 (2015 (1,25D), acts as a classic nuclear receptor ligand that binds specifically to the vitamin D receptor (VDR) to control the transcription of a multitude of genes, primarily those encoding proteins participating in bone mineral metabolism, regulating the immune system, and controlling cell growth and differentiation (1). Liganded VDR attracts one of the retinoid X receptors (RXRs) into a heterodimer that recognizes vitamin D responsive elements (VDREs) in the vicinity of target genes, regulating their expression via the recruitment of comodulator complexes that modify chromatin to effect either induction or repression of the cognate mRNA (2-4). A currently understudied area of vitamin D's function and significance is the CNS, even though the VDR protein is reportedly expressed broadly in the brain, including the neurons and glial cells (5). The most intense immunochemical signal is present in the hypothalamus (paraventricular and supraoptic nuclei and the lateral and ventromedial regions) and in the dopaminergic neurons of the substantia nigra (6). However, VDR protein is also detected in prefrontal cortex, cingulate gyrus, and CA2 region of the hippocampus. Thus, the VDR protein is clearly present in the CNS, but only limited information is available on the functions of VDR and its 1,25D ligand in the bra...

Gene Expression Profiling and Assessment of Vitamin D and Serotonin Pathway Variations in Patients With Irritable Bowel Syndrome

“…Interestingly, the IBS-C patients in this population were the most responsive to vitamin D supplementation in terms of a striking improvement across nearly all IBS symptoms. 47 Because IBS-C patients are thought to possess lower gut serotonin levels, 48 the responsiveness of these patients to vitamin D supplementation is consistent with the actions of vitamin D to raise gut TPH1/serotonin levels 25 and with our current hypothesis that vitamin D, via induction of the intestinal TPH1 gene, may play a role in IBS pathophysiology. While this study was limited by its small sample size, our IBS cohort displayed a trend toward diminished serum vitamin D levels relative to our non-IBS control group.…”

“…This analysis revealed that 10 of the 11 IBS patients tested exhibited decreased levels of TPH1 relative to a non-IBS sample population, although another study 37 found a statistically insignificant trend towards elevated TPH1 expression in IBS patients. The active hormonal metabolite of vitamin D has been shown to modulate serotonin production within neural 25 and colonic tissue (data not shown). In fact, vitamin D has been proposed as a potential treatment for IBS.…”

“…25 Taking this into account and considering the potential linkage between IBS and abnormal serotonin metabolism, we examined whether IBS patients exhibited lower serum levels of vitamin D. Nine of the eleven patient samples that were tested displayed 25(OH)D levels below 50 ng/mL (the range of vitamin D "sufficiency" has been previously defined as 30-60 ng/mL, with the most optimal levels ≥ 50 ng/mL 32 ). However, given our small sample size, this finding could have been affected by individual variance in sun-exposure, supplement intake, and overall body fat composition.…”

“…24 Moreover, in a recent report, the production of the rate-limiting enzyme in serotonin production, TPH, was significantly stimulated by the active hormonal vitamin D metabolite, 1,25-dihydroxyvitamin D (1,25D), in serotonergic neurons. 25 If IBS is linked to an imbalance in serotonin production, vitamin D could play a role in IBS pathogenesis and may provide novel insights into new modes of IBS management. Further, given the previously-discussed possible genetic etiology of IBS, we postulated that the vitamin D profile and individual transcriptome patterns from our patient cohort could be explored in an attempt to identify a more efficacious and cost-effective diagnostic model for IBS.…”

Breastfeeding and the gut-brain axis: is there a role for melatonin?

“…Using these co-abundance groups, these authors measured outcomes in regression models, with prenatal/birth and demographic characteristics as independent predictors, finding that race, mode of delivery, breastfeeding and cord blood vitamin D levels are significantly associated with the composition of the infant gut microbiome (45). Although such a single study does considerably simplify the associations of prenatal factors and breastfeeding with the infant's gut microbiome, it is important to note that variations in vitamin D may also modulate levels of serotonin availability for the melatonergic pathways, with vitamin D increasing levels of tryptophan hydroxylase and, therefore, serotonin synthesis (46). Other work supports a role for breastfeeding in the regulation of the gut microbiome, including in interaction with other factors, such as tobacco use and exposure to pets in pregnancy (47).…”