Abstract:
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
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Possible role of Neuromedin S in male reproductionGeneral Abstract
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 fasting-
induced 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
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Possible role of Neuromedin S in male reproductionGeneral Abstract
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.