| This dissertation focuses on the investigation of non-neuronal serotonin (5-HT) as a method to improve maternal metabolism during the transition from pregnancy to lactation. Our goal was to determine if the administration of the 5-HT precursor 5-hydroxy-L-tryptophan (5-HTP), would improve calcium (Ca) and energy status of the lactating mother. We demonstrated that 5-HT concentrations on day 1 of lactation were negatively associated with milk fever incidence and ketosis severity and positively associated with circulating Ca and parathyroid hormone related protein (PTHrP). Rodent models were used to dissect the molecular mechanisms behind 5-HT's actions. Feeding rats during their transition period (7 days pre-parturition to 9 days 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 (MG). In addition, feeding 5-HTP increased mRNA expression of enzymes involved in energy metabolism in the liver, and mRNA abundance and distribution of glucose transporters within the MG. We used a genetically modified mouse model deficient in non-neuronal 5-HT production (lack of the rate-limiting enzyme tryptophan hydroxylase, TPH1). Serotonin is necessary for proper MG structure and function and for the maintenance of Ca homeostasis in lactation. Particularly, 5-HT is critical for induction of PTHrP in the MG to induce maternal Ca mobilization from bone, and for mammary epithelial cell transport of Ca during lactation. We showed how 5-HT alters the methylation status of the sonic hedgehog (SHH) gene, resulting in induction of SHH mRNA expression to induce PTHrP expression that is necessary for bone Ca mobilization. Lastly, a 5-HTP dosing experiment was performed using non-pregnant late lactation dairy cows. Treatment of cows with 1.0 and 1.5 mg/kg of 5-HTP improved their energy metabolism, decreased loss of Ca into urine, and increased mammary uptake of Ca resulting in Ca secretion into milk. In summary, 5-HT is directly involved in the regulation of energy and Ca metabolism during lactation, and 5-HTP can be safely administered to dairy cattle. Our results support the hypothesis that 5-HT can be used for the prevention of hypocalcemia in dairy cows and possibly other metabolic disorders. |
