SAT-035 Neuromedin U Regulates Motivated Activity via Testosterone in Male Rats

Abstract Disclosure: S. Aizawa: None. M. Otsuka: None. Y. Takeuchi: None. M. Moriyama: None. S. Egoshi: None. S. Takeuchi: None. M. Matsuyama: None. G.E. Bentley: None. The objective of this study was to elucidate the role of endogenous Neuromedin U (NMU), a peptide hormone, in male rats by performing NMU knockout (KO). Although NMU administration is well known to be anorexigenic, our previous study demonstrated that NMU KO rats did not change their feeding amount and body weight. In the present study, we demonstrated that male NMU KO rats exhibited a reduction in wheel-running activity compared to wild-type (WT) rats. However, overall home cage activity remained unaltered. In addition, plasma testosterone levels in male WT rats exhibited a diurnal variation with a peak and a nadir, whereas in male NMU KO rats, these levels remained stable throughout the day. Furthermore, chronic administration of testosterone restored the wheel-running activity amount in male NMU KO rats to the same level as in male WT rats, suggesting that the decrease in wheel-running activity in male NMU KO rats is due to disruption of the daily variation of plasma testosterone concentration. In agreement with the reduction in daily testosterone variation, expression of the gonadotropin subunit LHb mRNA in the pars distalis of the pituitary was significantly reduced in male NMU KO rats as compared to male WT rats. Immunostaining revealed that the size of LH-expressing cells was relatively small in male NMU KO rats compared to male WT rats. In the hypothalamic-pituitary-gonadal axis of male WT rats, the expression levels of Nmu, NMU receptor types 1 (Nmur1) and 2 (Nmur2) were notably low in both the testis and the pars distalis of the pituitary. In the brain, Nmu demonstrated high expression in the pars tuberalis, while Nmur2 exhibited high expression in the ependymal cell layer of the third ventricle in male WT rats. These findings show locations of NMU action and suggest a potential impact of NMU deficiency on the hypothalamic regulatory system.This study reveals a novel function of NMU: that endogenous NMU in rats plays a role in the regulation of motivated activity via the regulation of testosterone. Presentation: Saturday, July 12, 2025