Possible Role of Neuromedin S in Male Reproduction

Abstract

Background: Neuromedin S (NMS), an anorexigenic neuropeptide was discovered in rat brain. It is a ligand for receptor FM4/TGR-1 which is also called as NMU receptor type II (NMU2R). Mainly it is expressed in SCN and involved in regulation of food intake and dark light circadian rhythms. In rodents its stimulatory role in HPG axis is reported but in higher primates its reproductive role is yet to be explored. In the present study the stimulatory role of NMS was investigated in the regulation of HPG axis and HPA axis. For this purpose after NMS administration plasma T and cortisol levels were determined in normal fed and 48-hrs fasting monkeys. Materials and methods: Four adult male rhesus monkeys were used in this study. Single dose of 50 nmol NMS was injected through a cannula affixed in saphenous vein. Blood samples were collected individually 60 min before and 120 min with 15 min intervals, after NMS/saline administration. In case of hCG administration, samples were collected 60 min before and 180 min at 15 min intervals, after hCG administration. Plasma T and cortisol concentrations were determined by using specific Enzyme Immunoassay (EIA) kits. Results: 48 hrs fasting significantly (P<0.001) decreased plasma T and increased cortisol (P<0.001) levels compared to normal fed monkeys. In both fed and fasting conditions, NMS injection induced a significant increase (P<0.05) in T and cortisol concentrations compared to saline treated animals. Conclusion: In summary our results suggested that NMS is a positive modulator of both HPG and HPA axis. In fasting conditions its effect on T secretion was delayed but in fed conditions no such response was observed suggesting that fasting has inhibitory role on HPG axis and NMS has ability to temporary terminate this inhibition. The exact pathway of its signaling is not clearly understood, so in future further studies are required to confirm the NMS involvement and its pathway in the regulation of reproductive axis.

Background: Neuromedin S (NMS), a 36 amino acid anorexigenic neuropeptide was discovered in rat brain. It is a ligand for receptor FM4/TGR-1 which is also called as NMU receptor type II (NMU2R). Mainly it is expressed in suprachiasmatic nucleus (SCN) and involved in regulation of food intake and dark light circadian rhythms. In rodents its stimulatory role in HPG axis is reported but in higher primates its reproductive role is yet to be explored. In present study we examined involvement of NMS-NMU2R signaling pathway in the metabolic regulation of the HPG axis in adult male rhesus monkey. We used three different approaches in this regard. First, we observed the peripheral effect of NMS on HPG axis in two metabolic states (normal fed and 48-hrs fasting) as it was known that metabolic status is key factor in HPG axis regulation. Second, we studied the role of NMS in HPA regulation and its influence on reproductive hormone secretion in male rhesus monkeys and third, we investigated the role of exogenous NMS on some other metabolic hormones which are involved directly or indirectly in the regulation of HPG axis. For this purpose various hormones concentrations such as testosterone (T), cortisol, growth hormone (GH), Prolactin (PRL), adiponectin, resistin, leptin and insulin were determined after NMS administration in normal fed and 48-hrs fasting monkeys. Materials and Methods: Four adult male rhesus monkeys (6-8 yr Age: 7-10 kg BW) were used in this study. Fifty nmol of NMS was injected through a cannula affixed in saphenous vein. Blood samples were collected individually at 15 min intervals, before and after NMS/saline/hCG administration. Plasma concentrations of T, cortisol, GH, PRL, adiponectin, leptin, resistin and insulin were estimated by using specific Enzyme Immunoassay (EIA) kits. Results: Short term fasting significantly (P<0.001) decreased T while increased cortisol concentrations. NMS induced significant (P<0.05) increase in T and cortisol concentrations in both fed and 48-hrs fasting monkeys. No significant (P>0.05) change was observed in saline treated animals. In fasting conditions T response to NMS was delayed and suppressed. 48-hrs fasting significantly (P<0.001) decreased PRL but did not affect GH levels significantly. NMS also induced significant (P<0.01) rise in GH levels in both fed and fasting conditions while PRL General Abstract Possible role of Neuromedin S in male reproduction 2 concentrations significantly (P<0.05) increased only in fed conditions. No significant change (P>0.05) in GH and PRL concentrations was noticed in saline treated animals. Short term fasting significantly increased (P<0.001) adiponectin concentrations while decreased leptin (p<0.001), resistin (P<0.01) and insulin (P<0.001) concentrations. NMS administration did not effect the adiponectin and insulin levels significantly (P>0.05) in both fed and fasting conditions. However NMS induced significant (P<0.01) increase in resistin levels, while suppressed leptin (P<0.01) secretion in both fed and 48-hrs fasting conditions. In saline treated animals no significant (P>0.05) changes in adiponectin, resistin, leptin and insulin levels were observed after saline administration. Discussion: Our results demonstrated that exogenous NMS administration rescues suppression of the HPG axis during conditions of metabolic fuels deficiency. In fasting conditions the NMS induced T response was both delayed and suppressed. Present results indicate that although NMS stimulated T secretion under fasting conditions, the response appears to be delayed and suppressed suggesting that fastinginduced suppression of the HPG axis in the adult male rhesus monkey may involve, at least in part, a reduction in the sensitivity of GnRH neuronal network to endogenous NMS stimulation. Cortisol is generally considered as negative regulator of HPG axis in males so it was assumed that in fasting conditions the delayed response of T secretion in present study is, due to the increased concentrations of cortisol. However in normal fed monkeys, elevated cortisol levels did not suppress T secretion. So it is not yet confirmed, whether increased cortisol levels caused suppression of T release or fasting itself has some deleterious effects on NMS expression in hypothalamus. In previous studies no association was found between cortisol and T secretion in monkeys. So it was concluded that in present study elevated cortisol levels are not responsible for delayed and suppressed T response to NMS. In our study increased GH and PRL secretions after NMS administration suggest that NMS exerts its regulatory actions on HPG axis and testicular steroidogenesis by affecting the secretions of these two pituitary hormones. Our results also demonstrated that exogenous NMS administration has no significant effect in the secretion of insulin and adiponectin but the same dose of NMS significantly inhibited leptin while General Abstract Possible role of Neuromedin S in male reproduction 3 stimulated plasma resistin levels. These findings suggest a potential involvement of NMS in the physiology of adipose tissue. Conclusion: NMS-NMU2R signaling appears to be critical in the regulation of reproductive axis in mammals including primates, during metabolically stressed conditions. Whether it is just another redundant pathway or the master conduit for relaying such information to GnRH neurons, the research will tell exactly very soon.