Central control of bone remodeling by neuromedin U

Bone remodeling, the function affected in osteoporosis, the most common of bone diseases, comprises two phases: bone formation by matrix-producing osteoblasts1 and bone resorption by osteoclasts2. The demonstration that the anorexigenic hormone leptin3–5 inhibits bone formation through a hypothalamic relay6,7 suggests that other molecules that affect energy metabolism in the hypothalamus could also modulate bone mass. Neuromedin U (NMU) is an anorexigenic neuropeptide that acts independently of leptin through poorly defined mechanisms8,9. Here we show that Nmu-deficient (Nmu–/–) mice have high bone mass owing to an increase in bone formation; this is more prominent in male mice than female mice. Physiological and cell-based assays indicate that NMU acts in the central nervous system, rather than directly on bone cells, to regulate bone remodeling. Notably, leptin- or sympathetic nervous system–mediated inhibition of bone formation6,7 was abolished in Nmu–/– mice, which show an altered bone expression of molecular clock genes (mediators of the inhibition of bone formation by leptin). Moreover, treatment of wild-type mice with a natural agonist for the NMU receptor decreased bone mass. Collectively, these results suggest that NMU may be the first central mediator of leptin-dependent regulation of bone mass identified to date. Given the existence of inhibitors and activators of NMU action10, our results may influence the treatment of diseases involving low bone mass, such as osteoporosis.

	NMU receptor type-1 (NMU1R) NMU receptor type-2 (NMU2R) FM-3/GPR66 FM-4/TGR-1 Peripheral tissues CNS: PVN & SCN NMU = NMS NMS > NMU

	Neuromedin U Neuromedin S Brain-gut neuropeptide Neuro & Immunopeptide Suppression of feeding Circadian rhythm regulation in the SCN Regulation of energy homeostasis Immune response in the spleen Elevation of arterial blood pressures and control of local blood flow Spermatogenesis in the testis

Sato S. et al. NATURE MEDICINE, published online 16 September 2007; doi:10.1038/nm1640

An Endogenous Ligands for Orphan G Protein-coupled Receptor, FM3 and FM4 with Central Control of Feeding

Neuromedin U (NMU) is a neuropeptide with potent activity on smooth muscle which was isolated first from porcine spinal cord and later from other species. It is widely distributed in the gut and central nervous system. Peripheral activities of NMU include stimulation of smooth muscle, increase of blood pressure, alteration of ion transport in the gut, control of local blood flow and regulation of adrenocortical function. An NMU receptor has not been molecularly identified. Here we show that the previously described orphan G-protein-coupled receptor FM-3 (ref. 15) and a newly discovered one (FM-4) are cognate receptors for NMU. FM-3, designated NMU1R, is abundantly expressed in peripheral tissues whereas FM-4, designated NMU2R, is expressed in specific regions of the brain. NMU is expressed in the ventromedial hypothalamus in the rat brain, and its level is significantly reduced following fasting. Intracerebroventricular administration of NMU markedly suppresses food intake in rats. These findings provide a molecular basis for the biochemical activities of NMU and may indicate that NMU is involved in the central control of feeding (Phoenix's Neuromedin U and other eighty-three peptides have been used in this research.)

HOWARD,A.D. et al. Identification of Receptors for Neuromedin U and its Role in Feeding. Nature 406, 70-75 (July 6, 2000).

NMU proprotein (104-136): A deorphan peptide ligand

The structural similarities of NMS and NMU on the gene and proprotein levels were observed among mouse, rat and human, indicating that the divergence of the two genes encoding these peptides preceded the rodent/primate split during the process of evolution. In addition, the NMS proprotein contains another novel 34-residue peptide, similar to the novel 33-residue peptide that Lo et al (1992) speculated to exist in the NMU proprotein. Indeed, we purified such an endogenous 33-residue peptide derived from the NMU proprotein from rat brain and small intestine extracts. Both synthetic 33- and 34-residue peptides derived from the NMU and NMS proproteins show potent prolactin-releasing activity upon ICV administration in rats.

The EMBO Journal (2005), 1–11

Anti Neuromedin U (Rat) antisera ( H-046-41) can be used for histochemistry mapping in rat brain tissues!!!

Expression of Neuromedin U (2.3 KDa) and Prepro-Neuromedin U (18 KDa) in the SD rat brain can be detected with Phoenix's Neuromedin U (Rat) Western Blot Kit (WBK-046-41)Visualization of  Neuromedin U Receptors (FM-3 & FM-4) with  FAM labeled Neuromedin U