Serotonin Regulates Calcium Homeostasis in Lactation by Epigenetic Activation of Hedgehog Signaling

Laporta, Jimena; Keil, Kimberly P.; Weaver, Samantha R.; Cronick, Callyssa M.; Prichard, A. P.; Crenshaw, Thomas D.; Heyne, Galen W.; Vezina, Chad M.; Lipinski, Robert J.; Hernández, Laura

doi:10.1210/me.2014-1204

Cited by 49 publications

(47 citation statements)

References 38 publications

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“…No literature has been found about the effect of 5-HT on the PTH receptors in the bone. Hernandez et al (2012) and Laporta et al (2014b) showed the stimulatory effect of increased 5-HT concentrations on the secretion of mammaryderived PTHrP in mice. As described in humans and mice, PTHrP acts on bone tissue to release calcium into the bloodstream (Wysolmerski, 2010).…”

Section: Discussionmentioning

confidence: 97%

Endocrine and metabolic changes in transition dairy cows are affected by prepartum infusions of a serotonin precursor

Hernández-Castellano

Hernández

Sauerwein

et al. 2017

Journal of Dairy Science

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Serotonin (5-HT) has been shown to be involved in calcium homeostasis, modulating calcium concentration in blood. In addition, 5-HT participates in a variety of metabolic pathways, mainly through the modulation of glucose and lipid metabolism. The hypothesis of the present study was that the prepartum administration of 5-hydroxy-l-tryptophan (5-HTP), a 5-HT precursor, would affect endocrine systems related to calcium homeostasis, and interact with other endocrine and metabolic pathways during the transition period. In this study, 20 Holstein dairy cows were randomly assigned to 2 experimental groups. Both groups received a daily i.v. infusion of 1 L of either 0.9% NaCl (control group; n = 10) or 0.9% NaCl containing 1 mg of 5-HTP/kg of BW (5-HTP group, n = 10). Infusions started d 10 before estimated parturition date and ended the day of parturition, resulting in a minimum of 4 d of infusion (8.4 ± 0.7 d of infusion). Until parturition, blood samples were collected before the daily infusions, and postpartum daily until d 7, and on d 30. Plasma concentrations of parathyroid hormone (PTH) were transiently increased at parturition and on d 1 in control cows. In the 5-HTP group PTH remained unchanged. The concentration of pyridinoline (PYD), an established marker for calcium release from the bone to the bloodstream, increased on d 1 postpartum only in the 5-HTP group. In control cows, PYD concentrations did not change on d 1 postpartum. Melatonin concentrations were slightly but significantly increased in the 5-HTP group compared with the control group. Insulin concentrations decreased in both groups postpartum. Before parturition, leptin concentrations decreased in both groups and remained at this level until d 30 postpartum. Plasma IgG concentrations decreased in both groups on d -1 postpartum. Haptoglobin increased in both groups on d -1 and remained at this level until d 7 postpartum. No differences between groups were observed for insulin, glucagon, IgG, leptin, adiponectin, and haptoglobin concentrations. The results obtained in the present study evidenced that 5-HT is regulating calcium homeostasis independent of PTH. The lack of treatment effects on IgG and on other hormones and metabolites indicates that 5-HTP did not affect these other metabolic pathways and the IgG concentration during the transition period.

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Section: Discussionmentioning

confidence: 97%

Endocrine and metabolic changes in transition dairy cows are affected by prepartum infusions of a serotonin precursor

Hernández-Castellano

Hernández

Sauerwein

et al. 2017

Journal of Dairy Science

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“…Serotonin plays a role in bone remodeling as it is required for osteoclastogenesis (Chabbi-Achengli et al, 2012), and it regulates Ca transport into mammary epithelial cells during lactation (Laporta et al, 2014a). In response to lactation, serotonin produced by the mammary gland triggers production of PTH-related protein that stimulates osteoclast activity and increased bone mobilization (Laporta et al, 2014b). Because DCAD was shown to influence serotonin as cows approached calving, and treatment with 1,25-dihydroxyvitamin D 3 immediately after calving has been shown to increase serotonin in dairy cows (Vieira-Neto et al, 2017), it is clear that these dietary interventions can influence endocrine signals that affect nutrient flux to the mammary gland.…”

Section: Discussionmentioning

confidence: 99%

Effects of prepartum dietary cation-anion difference and source of vitamin D in dairy cows: Vitamin D, mineral, and bone metabolism

Rodney

Martínez

Block³

et al. 2018

Journal of Dairy Science

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Pregnant Holstein cows, 28 nulliparous and 51 parous, were blocked by parity and milk yield and randomly allocated to receive diets that differed in dietary cation-anion difference (DCAD), +130 or -130 mEq/kg, and supplemented with either calcidiol or cholecalciferol at 3 mg/11 kg of dry matter from 255 d of gestation until parturition. Blood was sampled thrice weekly prepartum, and on d 0, 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, and 30 postpartum to evaluate effects of the diets on vitamin D, mineral and bone metabolism, and acid-base status. Blood pH and concentrations of minerals, vitamin D metabolites, and bone-related hormones were determined, as were mineral concentrations and losses in urine and colostrum. Supplementing with calcidiol increased plasma concentrations of 25-hydroxyvitamin D, 3-epi 25-hydroxyvitamin D, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and 24,25-dihydroxyvitamin D compared with supplementing with cholecalciferol. Cows fed the diet with negative DCAD had lesser concentrations of vitamin D metabolites before and after calving than cows fed the diet with positive DCAD, except for 25-hydroxyvitamin D. Feeding the diet with negative DCAD induced a compensated metabolic acidosis that attenuated the decline in blood ionized Ca (iCa) and serum total Ca (tCa) around calving, particularly in parous cows, whereas cows fed the diet with positive DCAD and supplemented with calcidiol had the greatest 1,25-dihydroxyvitamin D concentrations and the lowest iCa and tCa concentrations on d 1 and 2 postpartum. The acidogenic diet or calcidiol markedly increased urinary losses of tCa and tMg, and feeding calcidiol tended to increase colostrum yield and increased losses of tCa and tMg in colostrum. Cows fed the diet with negative DCAD had increased concentrations of serotonin and C-terminal telopeptide of type 1 collagen prepartum compared with cows fed the diet with positive DCAD. Concentrations of undercarboxylated and carboxylated osteocalcin and those of adiponectin did not differ with treatment. These results provide evidence that dietary manipulations can induce metabolic adaptations that improve mineral homeostasis with the onset of lactation that might explain some of the improvements observed in health and production when cows are fed diets with negative DCAD or supplemented with calcidiol.

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“…This secondarily upregulates TPH1/2, increasing 5HT synthesis while also decreasing 5HT degradation [ 28 ]. We have previously demonstrated an epigenetic-hedgehog link between 5HT and PTHrP involving DNA methylation [ 29 ]. However, 5HT has no donatable methyl groups, suggesting a secondary mechanism or indirect regulation of DNA methylation.…”

Section: Introductionmentioning

confidence: 99%

Serotonin stimulated parathyroid hormone related protein induction in the mammary epithelia by transglutaminase-dependent serotonylation

Sheftel

Hernández

2020

PLoS ONE

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Mammary-derived serotonin has been implicated in breast-to-bone communication during lactation by increasing parathyroid hormone related-protein (PTHrP) in the mammary gland. It is well established that PTHrP acts on the bone to liberate calcium for milk synthesis during lactation; however, the mechanism of serotonin’s regulation of PTHrP has not been fully elucidated. Recently, serotonylation has been shown to be involved in a variety of physiological processes mediated by serotonin. Therefore, we investigated whether serotonylation is involved in serotonin’s regulation of PTHrP in the mammary gland using lactogenically differentiated mouse mammary epithelial cells. We investigated the effect of increased intracellular serotonin using the antidepressant fluoxetine or 5-hydroxytryptophan (serotonin precursor), with or without transglutaminase inhibition and the corresponding action on PTHrP induction and activity. Treatment with fluoxetine or 5-hydroxytryptophan significantly increased intracellular serotonin concentrations and subsequently increased PTHrP gene expression, which was reduced with transglutaminase inhibition. Furthermore, we determined that transglutaminase activity is increased with lactogenic differentiation and 5-hydroxytryptophan or fluoxetine treatment. We investigated whether RhoA, Rac1, and Rab4 were potential serotonylation target proteins. We speculate that RhoA is potentially a serotonylation target protein. Our data suggest that serotonin regulates PTHrP induction in part through the process of serotonylation under lactogenic conditions in mouse mammary epithelial cells.

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Serotonin Regulates Calcium Homeostasis in Lactation by Epigenetic Activation of Hedgehog Signaling

Cited by 49 publications

References 38 publications

Endocrine and metabolic changes in transition dairy cows are affected by prepartum infusions of a serotonin precursor

Endocrine and metabolic changes in transition dairy cows are affected by prepartum infusions of a serotonin precursor

Effects of prepartum dietary cation-anion difference and source of vitamin D in dairy cows: Vitamin D, mineral, and bone metabolism

Serotonin stimulated parathyroid hormone related protein induction in the mammary epithelia by transglutaminase-dependent serotonylation

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