Decretins, hormones induced by fasting that suppress insulin production and secretion, have been postulated from classical human metabolic studies. From genetic screens, we identified Drosophila Limostatin (Lst), a peptide hormone that suppresses insulin secretion. Lst is induced by nutrient restriction in gut-associated endocrine cells. limostatin deficiency led to hyperinsulinemia, hypoglycemia, and excess adiposity. A conserved 15-residue polypeptide encoded by limostatin suppressed secretion by insulin-producing cells. Targeted knockdown of CG9918, a Drosophila ortholog of Neuromedin U receptors (NMURs), in insulin-producing cells phenocopied limostatin deficiency and attenuated insulin suppression by purified Lst, suggesting CG9918 encodes an Lst receptor. NMUR1 is expressed in islet ? cells, and purified NMU suppresses insulin secretion from human islets. A human mutant NMU variant that co-segregates with familial early-onset obesity and hyperinsulinemia fails to suppress insulin secretion. We propose Lst as an index member of an ancient hormone class called decretins, which suppress insulin output.
Bone remodeling, the function affected in osteoporosis, the most common of bone diseases, comprises two phases: bone formation by matrix-producing osteoblasts and bone resorption by osteoclasts. The demonstration that the anorexigenic hormone leptin inhibits bone formation through a hypothalamic relay 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 mechanisms. 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 formation 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 action, 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
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.
This publication used a Neuromedin U peptide, as well as 83 other peptides, from Phoenix Pharmaceuticals.
The discovery of neuropeptides has resulted in an increased understanding of novel regulatory mechanisms of certain physiological phenomena. Here we identify a novel neuropeptide of 36 amino-acid residues in rat brain as an endogenous ligand for the orphan G protein-coupled receptor FM-4/TGR-1, which was identified to date as the neuromedin U (NMU) receptor, and designate this peptide ‘neuromedin S (NMS)' because it is specifically expressed in the suprachiasmatic nuclei (SCN) of the hypothalamus. NMS shares a C-terminal core structure with NMU. The NMS precursor contains another novel peptide. NMS mRNA is highly expressed in the central nervous system, spleen and testis. In rat brain, NMS expression is restricted to the core of the SCN and has a diurnal peak under light/dark cycling, but remains stable under constant darkness. Intracerebroventricular administration of NMS in rats activates SCN neurons and induces nonphotic type phase shifts in the circadian rhythm of locomotor activity. These findings suggest that NMS in the SCN is implicated in the regulation of circadian rhythms through autocrine and/or paracrine actions.
|046-65||Neuromedin U-23 (Mouse)||100 µg||$194|
|046-42||Neuromedin U-25 (Human)||200 µg||$163|
|046-33||Limostatin-15 (LST-15)||100 µg||$153|
|046-30||NMUR2 Selective Agonist 6b||100 µg||$122|
|045-96||NURP33 / prepro-Neuromedin U (104-136) (Human)||100 µg||$214|
|045-97||NURP33 / prepro-Neuromedin U (106-138) (Rat, Mouse)||100 µg||$214|
|046-76||NURP36 / prepro-Neuromedin U (104-139) (Human)||100 µg||$163|
|H-045-96||prepro-Neuromedin U (104-136) (Human) - Antibody||100 µl||$459|
|B-045-96||prepro-Neuromedin U (104-136) (Human) - Biotin Labeled||10 µg||$306|
|B-G-045-96||prepro-Neuromedin U (104-136) (Human) - Biotin Labeled Purified IgG||100 µl||$505|
|FC3-G-045-96||prepro-Neuromedin U (104-136) (Human) - Cy3 Labeled Purified IgG||100 µl||$607|
|FG-045-96A||prepro-Neuromedin U (104-136) (Human) - FAM Labeled||1 nmol||$306|
|FG-G-045-96A||prepro-Neuromedin U (104-136) (Human) - FAM Labeled Purified IgG||100 µl||$505|
|FG-G-045-96B||prepro-Neuromedin U (104-136) (Human) - FITC Labeled Purified IgG||100 µl||$505|
|T-045-96||prepro-Neuromedin U (104-136) (Human) - I-125 Labeled||10 µCi||$723|
|T-G-045-96||prepro-Neuromedin U (104-136) (Human) - I-125 Labeled Purified IgG||10 µCi||$723|
|G-045-96||prepro-Neuromedin U (104-136) (Human) - Purified IgG Antibody||200 µg||$459|
|RK-045-96||prepro-Neuromedin U (104-136) (Human) - RIA Kit||125 tubes||$588|
|FR-045-96||prepro-Neuromedin U (104-136) (Human) - Rhodamine Labeled||1 nmol||$357|
|046-54||prepro-Neuromedin U (106-141) (Rat, Mouse)||100 µg||$194|
|046-41||Neuromedin U (Rat)||200 µg||$61|
|H-046-41||Neuromedin U (Rat) - Antibody||50 µl||$459|
|B-G-046-41||Neuromedin U (Rat) - Biotin Labeled Purified IgG||100 µl||$459|
|DBK-046-41||Neuromedin U (Rat) - Dot Blot Kit||5 blots||$612|
|FG-046-41A||Neuromedin U (Rat) - FAM Labeled||1 nmol||$408|
|FG-G-046-41A||Neuromedin U (Rat) - FAM Labeled Purified IgG||100 µl||$459|
|T-046-41||Neuromedin U (Rat) - I-125 Labeled||10 µCi||$723|
|T-G-046-41||Neuromedin U (Rat) - I-125 Labeled Purified IgG||10 µCi||$723|
|G-046-41||Neuromedin U (Rat) - Purified IgG Antibody||200 µg||$459|
|RK-046-41||Neuromedin U (Rat) - RIA Kit||125 tubes||$671|