Endocrine Abstracts (2002) 3 OC48

Hypothalamic actions of Neuromedin U

AM Wren, CJ Small, CR Abbott, MA Ghatei & SR Bloom

Department of Metabolic Medicine, Imperial College of Science Technology and Medicine, Hammersmith Campus, London, UK.

The CNS and gut derived peptide Neuromedin U (NMU) has been shown to inhibit feeding following intracerebroventricular (ICV) injection. The present study aimed to further explore the hypothalamic actions of NMU. ICV NMU-23 (1nmol), but not truncated NMU-8, significantly inhibited feeding (1h food intake: 3.8 plus/minus 0.4g vs saline 5.4 plus/minus 0.6g, p <0.05). Following micro-injection into 8 hypothalamic areas, NMU-23 potently inhibited feeding in the PVN (1h food intake: 3.5 plus/minus 0.5g vs saline 5.9 plus/minus 0.3g, p<0.001). Corticotrophin releasing hormone (CRH) has also been implicated in feeding inhibition and is synthesized in the PVN, the sole hypothalamic site of NMU receptor expression. NMU stimulates steroid secretion at the adrenal level, but the action of NMU on the hypothalamo-pituitary adrenal (HPA) axis at the hypothalamic level has not been investigated. In the current study PVN administration of NMU-23 (1nmol) increased plasma ACTH (39.2 plus/minus 5.9 pg/ml vs. saline 12.2 plus/minus 2.6 pg/ml) and corticosterone (303.6 plus/minus 21.6 vs saline 171.0 plus/minus 20.9 ng/ml). Using hypothalamic explants in vitro, NMU stimulated CRH release (8.0 plus/minus 1.8 pmol/explant vs. basal 5.0 plus/minus 1.3 pmol/explant, p<0.05). NMU release from hypothalamic explants was itself stimulated by the adipocyte-derived satiety signal leptin (141.9 plus/minus 20.4 fmol/explant vs. basal 92.9 plus/minus 9.4 fmol/explant, p<0.01). Thus we describe a novel role for NMU acting on the PVN to stimulate the HPA axis and to inhibit feeding. NMU is responsive to leptin and appears to act, at least in part, via CRH.

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