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The role of serotonin (5-HT) in calcium and energy homeostasis during lactation
We investigated the role of non-neuronal serotonin (5-hydroxytryptamine, 5-HT) on the regulation of maternal calcium (Ca) and energy status during lactation. We demonstrated that circulating concentrations of 5-HT on day 1 of lactation in Holstein dairy cows was negatively associated with milk fever incidence and ketosis severity, and was positively associated with circulating Ca and parathyroid hormone related protein (PTHrP). To evaluate the feasibility of manipulating this pathway, we administered a 5-HT precursor, 5-hydroxy-L-tryptophan (5-HTP), through alteration of the maternal diet using rodent models. Feeding rats during their transition period (7 d pre- to 9 d post-parturition) with 5-HTP improved maternal Ca homeostasis during lactation, by increasing mammary PTHrP, bone Ca mobilization and Ca uptake by the mammary gland. In addition, feeding 5-HTP increased mRNA expression of hepatic enzymes involved in energy metabolism, and of glucose transporters within the mammary gland. A genetically modified mouse model (deficient in non-neuronal 5-HT production due to the lack of the rate-limiting enzyme tryptophan hydroxylase, TPH1) was used to demonstrate that 5-HT is necessary for proper mammary gland structure and function, and for the maintenance of Ca homeostasis in the early post-partum period. In particular, 5-HT is critical for induction of PTHrP in the mammary gland to induce maternal calcium mobilization from bone, and for mammary epithelial cell transport of Ca during lactation. We further determined that 5-HT alters methylation status of the sonic hedgehog (SHH) gene, resulting in induction of SHH mRNA expression to induce PTHrP expression, which is necessary for bone Ca mobilization. Lastly, a 5-HTP dosing experiment was performed using non-pregnant late lactation dairy cow model. Treatment of late-lactation dairy cows with 1.0 and 1.5 mg/kg of 5-HTP improves their energy metabolism, decreases loss of Ca into urine, and increases mammary uptake of Ca resulting in increased Ca secretion into milk. The major findings of this research are that 5-HT is directly involved in the regulation of energy and Ca metabolism during lactation, and that 5-HTP can be safely administered to dairy cattle. We need to understand how manipulating the serotonergic system during the transition period in dairy cows impacts maternal Ca and glucose metabolism. Our data supports the hypothesis that 5-HT can be a therapeutic target for prevention of hypocalcemia in dairy cows and possibly other metabolic disorders during lactation.
Keywords: Sertotonin, calcium, glucose, mammary gland, liver, lactation