Central actions of neuromedin U via corticotropin-releasing hormone

Hanada, Takeshi; Date, Yukari; Shimbara, Takuya; Sakihara, Satoru; Murakami, Noboru; Hayashi, Yujiro; Kanai, Yasushi; Suda, Toshio; Kangawa, Kenji; Nakazato, Masamitsu

doi:10.1016/j.bbrc.2003.10.098

Cited by 96 publications

(77 citation statements)

References 30 publications

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“…In conclusion, this study clarified that (1) the novel hexapeptide derivative, 5d (designated CPN-170; CPN, Cterminal core peptide derivative of neuromedin U) displayed potent agonistic activity toward human NMU receptors, especially NMUR1; (2) our hexapeptide derivatives were hydrolyzed at two major cleavage sites (the Arg 5 -Asn 6 and Phe 2 -Arg 3 bonds) in rat serum; (3) the Arg 5 -Asn 6 bond was preferentially cleaved as compared to the Phe 2 -Arg 3 bond; (4) introduction of a fluorine atom at the 4-position of Phe in 4d significantly stabilized the Phe 2 -Arg 3 bond; and (5) N-terminal structural modifications at the acyl group, residues 1 and 2 influenced not only the agonistic activity but also the metabolic stability of both cleavage sites. In practical terms, stabilization of the Arg 5 -Asn 6 bond will be necessary to exert a long-lasting anorexigenic effect in vivo.…”

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confidence: 70%

“…Therefore, in the present study, in order to develop more potent agonists, we performed additional SAR work and found agonist 5d, with potent activity and similar NMUR1-agonistic activity to hNMU. Moreover, we performed stability studies in rat and human serum to assess the biodegradation of the synthesized agonists and found that they were cleaved at two positions: Phe 2 -Arg 3 and Arg 5 -Asn 6 . The amide bond of the Arg 5 -Asn 6 site was more preferentially cleaved.…”

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confidence: 99%

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Discovery of Potent Hexapeptide Agonists to Human Neuromedin U Receptor 1 and Identification of Their Serum Metabolites

Takayama

Mori

Sohma

et al. 2015

ACS Med. Chem. Lett.

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Neuromedin U (NMU) and S (NMS) display various physiological activities, including an anorexigenic effect, and share a common C-terminal heptapeptide-amide sequence that is necessary to activate two NMU receptors (NMUR1 and NMUR2). On the basis of this knowledge, we recently developed hexapeptide agonists 2 and 3, which are highly selective to human NMUR1 and NMUR2, respectively. However, the agonists are still less potent than the endogenous ligand, hNMU. Therefore, we performed an additional structure−activity relationship study, which led to the identification of the more potent hexapeptide 5d that exhibits similar NMUR1-agonistic activity as compared to hNMU. Additionally, we studied the stability of synthesized agonists, including 5d, in rat serum, and identified two major biodegradation sites: Phe 2 -Arg 3 and Arg 5 -Asn 6 . The latter was more predominantly cleaved than the former. Moreover, substitution with 4-fluorophenylalanine, as in 5d, enhanced the metabolic stability at Phe 2 -Arg 3 . These results provide important information to guide the development of practical hNMU agonists.

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confidence: 70%

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confidence: 99%

Discovery of Potent Hexapeptide Agonists to Human Neuromedin U Receptor 1 and Identification of Their Serum Metabolites

Takayama

Mori

Sohma

et al. 2015

ACS Med. Chem. Lett.

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“…Mice deficient in CRH do not show NMU-suppressed feeding or NMU-induced increases in oxygen consumption or body temperature [25]. A CRH antagonist abolishes the effects of NMU on locomotor activity [23], and NMU stimulates the release of CRH in hypothalamic explants [96].…”

Section: Discussionmentioning

confidence: 99%

“…Here, we examined NMU, a neuropeptide that modulates physical activity through its actions on brain regions that integrate signals relating to energy balance and body weight [40,42,48,71,73,85,87]. Because NMU affects energy balance through changes in both energy intake [24,25,34,37,44,69,96] and expenditure [17,[23][24][25]88,96], in part through increases in physical activity [24,69,73], we examined how NMU affects physical activity in obese and non-obese rats.…”

Section: Discussionmentioning

confidence: 99%

Sensitivity of the hypothalamic paraventricular nucleus to the locomotor-activating effects of neuromedin U in obesity

2007

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Obesity is associated with a decrease in energy expenditure relative to energy intake. The decrease in physical activity associated with obesity in several species, including humans, contributes to decreased energy expenditure. Several hormones and neuropeptides that affect appetite also modulate physical activity, including neuromedin U (NMU), a peptide found in the gut and brain. We have demonstrated that NMU microinjected into the hypothalamic paraventricular nucleus (PVN) in rats increases the energy expenditure associated with physical activity, called non-exercise activity thermogenesis (NEAT). Here we examined whether obesity in rats is related to decreased sensitivity of the PVN to the locomotor-activating effect of NMU. Diet-induced obese (DIO) rats and lean, dietresistant (DR) rats were given PVN microinjections of increasing doses of NMU both before and after one month on a high-fat diet. We found that NMU increases physical activity, energy expenditure, and NEAT in a dose-dependent manner in both DR and DIO rats, both before and after one month on the high-fat diet. Before high-fat feeding, the obesity-prone and lean rats showed similar levels of physical activity after intra-PVN microinjections of NMU. After one month of the high-fat diet, however, the obesity-resistant rats showed significantly more NMU-induced physical activity compared to the obese DIO rats. Taken together with previous studies, these results suggest that obesity may represent a state associated with decreased central sensitivity to neuropeptides such as NMU that increase physical activity and therefore energy expenditure.

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“…Hypothalamic NMU mRNA levels are significantly reduced following fasting [72]. ICV administration of NMU reduces food intake in mice [73] and rats [72]. NMU administration also increases both physical activity and non-exercise activity thermogenesis in both DIO and lean rats [74].…”

Section: Neuromedin Umentioning

confidence: 99%

Peptides and Their Potential Role in the Treatment of Diabetes and Obesity

Greenwood

Bloom²,

Murphy

2011

Rev Diabet Stud

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■ AbstractIt is estimated that 347 million people worldwide have diabetes and that over 1.5 billion adults worldwide are overweight. Predictions suggest these rates are increasing. Diabetes is a common complication in overweight and obese subjects, and in 2004, an estimated 3.4 million people died from consequences of high blood sugar. Thus, there is great interest in revealing the physiological systems that regulate body weight and blood sugar. Several peptidergic systems within the central nervous system and the periphery regulate energy homeostasis. A number of these systems have been investigated as potential treatments for obesity and the metabolic syndrome. However, manipulation of peptidergic systems poses many problems. This review discusses the peptidergic systems currently attracting research interest for their clinical potential to treat obesity. We consider first neuropeptides in the brain, including the orexigenic neuropeptide Y and melanin-concentrating hormone, and anorectic factors such as the melanocortins, ciliary neurotrophic factor, and neuromedin U. We subsequently discuss the utility of targeting peripheral gut peptides, including pancreatic polypeptide, peptide YY, amylin, and the gastric hormone ghrelin. Also, we analyze the evidence that these factors or drugs based on them may be therapeutically useful, while considering the disadvantages of using such peptides in a clinical context.

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Central actions of neuromedin U via corticotropin-releasing hormone

Cited by 96 publications

References 30 publications

Discovery of Potent Hexapeptide Agonists to Human Neuromedin U Receptor 1 and Identification of Their Serum Metabolites

Discovery of Potent Hexapeptide Agonists to Human Neuromedin U Receptor 1 and Identification of Their Serum Metabolites

Sensitivity of the hypothalamic paraventricular nucleus to the locomotor-activating effects of neuromedin U in obesity

Peptides and Their Potential Role in the Treatment of Diabetes and Obesity

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