RESUMO
A 4×4 Latin square design in which varied doses (0, 0.5, 1.0, and 1.5âmg/kg) of 5-hydroxy-l-tryptophan (5-HTP, a serotonin precursor) were intravenously infused into late-lactation, non-pregnant Holstein dairy cows was used to determine the effects of serotonin on calcium and energy metabolism. Infusion periods lasted 4 days, with a 5-day washout between periods. Cows were infused at a constant rate for 1âh each day. Blood was collected pre- and 5, 10, 30, 60, 90, and 120âmin post-infusion, urine was collected pre- and post-infusion, and milk was collected daily. All of the 5-HTP doses increased systemic serotonin as compared to the 0âmg/kg dose, and the 1.0 and 1.5âmg/kg doses increased circulating glucose and non-esterified fatty acids (NEFA) and decreased beta-hydroxybutyrate (ßHBA) concentrations. Treatment of cows with either 1.0 or 1.5âmg/kg 5-HTP doses decreased urine calcium elimination, and the 1.5âmg/kg dose increased milk calcium concentrations. No differences were detected in the heart rates, respiration rates, or body temperatures of the cows; however, manure scores and defecation frequency were affected. Indeed, cows that received 5-HTP defecated more, and the consistency of their manure was softer. Treatment of late-lactation dairy cows with 5-HTP improved energy metabolism, decreased loss of calcium into urine, and increased calcium secretion into milk. Further research should target the effects of increasing serotonin during the transition period to determine any benefits for post-parturient calcium and glucose metabolism.
Assuntos
Cálcio/metabolismo , Metabolismo Energético , Serotonina/metabolismo , Ácido 3-Hidroxibutírico/sangue , 5-Hidroxitriptofano/administração & dosagem , Animais , Glicemia/metabolismo , Cálcio/sangue , Cálcio/urina , Bovinos , Metabolismo Energético/efeitos dos fármacos , Ácidos Graxos não Esterificados/sangue , Feminino , Expressão Gênica/efeitos dos fármacos , Insulina/sangue , Lactação , Fígado/efeitos dos fármacos , Fígado/metabolismo , Leite/efeitos dos fármacos , Leite/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/sangue , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Serotonina/sangueRESUMO
Calcium homeostasis during lactation is critical for maternal and neonatal health. We previously showed that nonneuronal/peripheral serotonin [5-hydroxytryptamine (5-HT)] causes the lactating mammary gland to synthesize and secrete PTHrP in an acute fashion. Here, using a mouse model, we found that genetic inactivation of tryptophan hydroxylase 1 (Tph1), which catalyzes the rate-limiting step in peripheral 5-HT synthesis, reduced circulating and mammary PTHrP expression, osteoclast activity, and maternal circulating calcium concentrations during the transition from pregnancy to lactation. Tph1 inactivation also reduced sonic hedgehog signaling in the mammary gland during lactation. Each of these deficiencies was rescued by daily injections of 5-hydroxy-L-tryptophan (an immediate precursor of 5-HT) to Tph1-deficient dams. We used immortalized mouse embryonic fibroblasts to demonstrate that 5-HT induces PTHrP through a sonic hedgehog-dependent signal transduction mechanism. We also found that 5-HT altered DNA methylation of the Shh gene locus, leading to transcriptional initiation at an alternate start site and formation of a variant transcript in mouse embryonic fibroblasts in vitro and in mammary tissue in vivo. These results support a new paradigm of 5-HT-mediated Shh regulation involving DNA methylation remodeling and promoter switching. In addition to having immediate implications for lactation biology, identification and characterization of a novel functional regulatory relationship between nonneuronal 5-HT, hedgehog signaling, and PTHrP offers new avenues for the study of these important factors in development and disease.