Identification of a degrading enzyme in human serum that hydrolyzes a C‐terminal core sequence of neuromedin U

Takayama, Kentaro; Taguchi, Akihiro; Yakushiji, Fumika; Hayashi, Yoshio

doi:10.1002/bip.22770

Cited by 15 publications

(26 citation statements)

References 25 publications

(52 reference statements)

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“…Moreover, it was reported that the preferential biodegradation site of this NMUR1 selective agonist was located between the Arg and Asn residues and that the key enzyme, responsible for this cleavage, was found to be thrombin [20,36]. The present study is giving more accurate information when compared to studies where experiments were performed with 25% rat or human serum [19,20]…”

Section: In Vitro Plasma Stabilitymentioning

confidence: 62%

Development of potent and proteolytically stable human neuromedin U receptor agonists

Prins

Martin

Wanseele

et al. 2018

European Journal of Medicinal Chemistry

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Neuromedin U (NMU) is a highly conserved endogenous peptide that is involved in a wide range of physiological processes such as regulation of feeding behavior, the stress response and nociception. The major limitation to use NMU as a therapeutic is its short half-life. Here, we describe the development of a set of novel NMU-analogs based on NMU-8, by introducing unnatural amino acids into the native sequence. This approach shows that it is possible to generate molecules with increased potency and improved plasma stability without major changes of the peptidic nature or the introduction of large conjugates. When compared to the native NMU-8 peptide, compounds 16, 18 and 20 have potent agonist activity and affinity for both NMU receptors. Selectivity towards NMUR1 was observed when the Phe residue in position 4 was modified, whereas higher potencies at NMUR2 were found when substitutions of the Pro residue in position 6 were executed. To study the effect of the modifications on the proteolytic stability of the molecules, an in vitro stability assay in human plasma at 37 °C was performed. All analyzed analogs possessed an increased resistance against enzymatic degradation in human plasma resulting in half-lifes from 4 min for NMU-8, up to more than 23 h for compound 42.

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Section: In Vitro Plasma Stabilitymentioning

confidence: 62%

Development of potent and proteolytically stable human neuromedin U receptor agonists

Prins

Martin

Wanseele

et al. 2018

European Journal of Medicinal Chemistry

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“…Finally, we detected endogenous secretion of NMU in response to a mixed meal, showing that NMU can be considered as an enteropeptide. After a mixed meal, NMU was only detected in the portal vein that receives peptide secretions from the gut and not in the general blood circulation, confirming its rapid degradation (33). In addition, and as recently reported by Kuhre et al .…”

Section: Discussionmentioning

confidence: 91%

Neuromedin U is a gut peptide that alters oral glucose tolerance by delaying gastric emptying via direct contraction of the pylorus and vagal‐dependent mechanisms

et al. 2019

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The gut‐brain peptide neuromedin U (NMU) decreases food intake and body weight and improves glucose tolerance. Here, we characterized NMU as an enteropeptide and determined how it impacts glucose excursion. NMU was expressed predominantly in the proximal small intestine, and its secretion was triggered by ingestion of a mixed meal. Although a single peripheral injection of NMU in C57BL/6NRj mice prevented the rise of glycemia upon an oral but not an intraperitoneal load of glucose, it unexpectedly prevented insulin secretion, only slightly improved peripheral insulin sensitivity, and barely reduced intestinal glucose absorption. Interestingly, peripheral administration of NMU abrogated gastric emptying. NMU receptors 1 and 2 were detected in pyloric muscles and NMU was able to directly induce pyloric contraction in a dose‐dependent manner ex vivo in isometric chambers. Using a modified glucose tolerance test, we demonstrate that improvement of oral glucose tolerance by NMU was essentially, if not exclusively, because of its impact on gastric emptying. Part of this effect was abolished in vagotomized (VagoX) mice, suggesting implication of the vagus tone. Accordingly, peripheral injection of NMU was associated with increased number of c‐FOS–positive neurons in the nucleus of the solitary tract, which was partly prevented in VagoX mice. Finally, NMU kept its ability to improve oral glucose tolerance in obese and diabetic murine models. Together, these data demonstrate that NMU is an enteropeptide that prevents gastric emptying directly by triggering pylorus contraction and indirectly through vagal afferent neurons. This blockade consequently reduces intestinal nutrient absorption and thereby results in an apparent improved tolerance to oral glucose challenge.—Jarry, A.‐C., Merah, N., Cisse, F., Cayetanot, F., Fiamma, M.‐N., Willemetz, A., Gueddouri, D., Barka, B., Valet, P., Guilmeau, S., Bado, A., Le Beyec, J., Bodineau, L., Le Gall, M. Neuromedin U is a gut peptide that alters oral glucose tolerance by delaying gastric emptying via direct contraction of the pylorus and vagal‐dependent mechanisms. FASEB J. 33, 5377–5388 (2019). http://www.fasebj.org

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“…We here show that intra‐NAc NMU attenuates acute and chronic effects of alcohol; however, the origin of NMU detected in the NAc could include neuronal production or peripheral release. As the circulating NMU levels are low due to rapid degradation, the possibility that NMU is produced locally in distinct brain regions appears more likely. NMU coreleasing afferents of the lateral hypothalamus, an area that regulates drug reinforcement through its NAc projection, may provide one tentative origin.…”

Section: Discussionmentioning

confidence: 99%

Brain region‐specific neuromedin U signalling regulates alcohol‐related behaviours and food intake in rodents

2019

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Albeit neuromedin U (NMU) attenuates alcohol-mediated behaviours, its mechanisms of action are poorly defined. Providing that the behavioural effects of alcohol are processed within the nucleus accumbens (NAc) shell, anterior ventral tegmental area (aVTA), and laterodorsal tegmental area (LDTg), we assessed the involvement of NMU signalling in the aforementioned areas on alcohol-mediated behaviours in rodents. We further examined the expression of NMU and NMU receptor 2 (NMUR2) in NAc and the dorsal striatum of high compared with low alcoholconsuming rats, as this area is of importance in the maintenance of alcohol use disorder (AUD). Finally, we investigated the involvement of NAc shell, aVTA and LDTg in the consumption of chow and palatable peanut butter, to expand the link between NMU and reward-related behaviours. We demonstrated here, that NMU into the NAc shell, but not aVTA or LDTg, blocked the ability of acute alcohol to cause locomotor stimulation and to induce memory retrieval of alcohol reward, as well as reduced peanut butter in mice. In addition, NMU into NAc shell decreased alcohol intake in rats. On a molecular level, we found increased NMU and decreased NMUR2 expression in the dorsal striatum in high compared with low alcoholconsuming rats. Both aVTA and LDTg, rather than NAc shell, were identified as novel sites of action for NMU's anorexigenic properties in mice based on NMU's ability to selectively reduce chow intake when injected to these areas. Collectively, these data indicate that NMU signalling in different brain areas selectively modulates different behaviours.

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Identification of a degrading enzyme in human serum that hydrolyzes a C‐terminal core sequence of neuromedin U

Cited by 15 publications

References 25 publications

Development of potent and proteolytically stable human neuromedin U receptor agonists

Development of potent and proteolytically stable human neuromedin U receptor agonists

Neuromedin U is a gut peptide that alters oral glucose tolerance by delaying gastric emptying via direct contraction of the pylorus and vagal‐dependent mechanisms

Brain region‐specific neuromedin U signalling regulates alcohol‐related behaviours and food intake in rodents

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