Localisation of NMU1R and NMU2R in human and rat central nervous system and effects of neuromedin-U following central administration in rats

Gartlon, Jane; Szekeres, Philip G.; Pullen, Mark; Sarau, Henry M.; Aiyar, Nambi; Shabon, Usman; Michalovich, David; Steplewski, Klaudia; Ellis, Cathy; Elshourbagy, Nabil A.; Duxon, Mark S.; Ashmeade, Tracey; Harrison, David; Murdock, Paul R.; Wilson, Shelagh; Ennaceur, Abdelkader; Atkins, A.R.; Heidbreder, Christian; Hagan, Jim J.; Hunter, A. Jackie; Jones, Declan N.C.

doi:10.1007/s00213-004-1918-3

Cited by 53 publications

(80 citation statements)

References 41 publications

(80 reference statements)

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“…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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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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“…Indeed, i.c.v. administration of NmU to rats induced stress-related behavior (37,(63)(64)(65)(66). This was coupled to an increase in c-Fos expression, increased depolarization, and neuronal firing by cells of the PVN following NmU administration (67)(68)(69)(70)(71).…”

Section: Stress Responsementioning

confidence: 96%

Neuromedin U: A Multifunctional Neuropeptide with Pleiotropic Roles

2015

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BACKGROUND Neuromedin U (NmU) belongs to the neuromedin family, comprising a series of neuropeptides involved in the gut–brain axis and including neuromedins B and C (bombesin-like), K (neurokinin B), L (neurokinin A or neurotensin), N, S, and U. CONTENT Although initially isolated from porcine spinal cord on the basis of their ability to induce uterine smooth muscle contraction, these peptides have now been found to be expressed in several different tissues and have been ascribed numerous functions, from appetite regulation and energy balance control to muscle contraction and tumor progression. NmU has been detected in several species to date, particularly in mammals (pig, rat, rabbit, dog, guinea pig, human), but also in amphibian, avian, and fish species. The NmU sequence is highly conserved across different species, indicating that this peptide is ancient and plays an important biological role. Here, we summarize the main structural and functional characteristics of NmU and describe its many roles, highlighting the jack-of-all-trades nature of this neuropeptide. SUMMARY NmU involvement in key processes has outlined the possibility that this neuropeptide could be a novel target for the treatment of obesity and cancer, among other disorders. Although the potential for NmU as a therapeutic target is obvious, the multiple functions of this molecule should be taken into account when designing an approach to targeting NmU and/or its receptors.

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“…The effective concentrations of p-synephrine were from 0.227 to 1000 µmol/L. And in this analysis systems, NMU efficacy, EC 50 …”

Section: Identification Of P-synephrine As a Nmu2r Agonist Inmentioning

confidence: 69%

“…26) Efficacy is a measure of the maximum biological effect that a drug can produce as a result of receptor binding. Potency of a drug refers to the amount of drug required to achieve a defined biological effect-the smaller the dose required, the more potent the drug, which is the same with EC 50 . 27,28) The p-synephrine targeting NMU2R efficacy, EC 50 , and potency values were 7.207, 6.604, 0.227 µmol/L, respectively, which manifested the high potency and high efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…Potency of a drug refers to the amount of drug required to achieve a defined biological effect-the smaller the dose required, the more potent the drug, which is the same with EC 50 . 27,28) The p-synephrine targeting NMU2R efficacy, EC 50 , and potency values were 7.207, 6.604, 0.227 µmol/L, respectively, which manifested the high potency and high efficacy. And the potency and efficacy of p-synephrine are essentially the same with that of NMU by this screening system.…”

Section: Discussionmentioning

confidence: 99%

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<i>p</i>-Synephrine: A Novel Agonist for Neuromedin U2 Receptor

Zheng

Guo

Wang

et al. 2014

Biological & Pharmaceutical Bulletin

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In the brain, Neuromedin U2 receptor (NMU2R) is prominent in the hypothalamic regions and is known to be associated with regulation of several important physiological functions, including food intake, energy balance, stress response, and nociception. In this article, by random screening of compounds using the model of high-throughput screening for NMU2R stable expression, NMU2R negative and NMU2R short hairpin RNA (shRNA) knockdown HEK293 cell lines, for the first time, we discovered that p-synephrine, which is the primary protoalkaloid in Citrus aurantium (bitter orange) and is widely used in weight loss and weight management products, is a highly potent and selective NMU2R agonist. In NMU2R activating ability experiments, p-synephrine was found binding to NMU2R with high efficacy and potency; the efficacy, 50% of the maximum possible effect (EC 50 ) and potency values were determined to be 7.207, 6.604 and 0.227 µmol/L for the NMU2R, respectively. Our researches have important theoretical value for elucidating the mechanisms of p-synephrine in body weight and energy balance regulation. These data provide further evidence for widespread roles for p-synephrine and its receptors in the brain.

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Localisation of NMU1R and NMU2R in human and rat central nervous system and effects of neuromedin-U following central administration in rats

Cited by 53 publications

References 41 publications

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

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

Neuromedin U: A Multifunctional Neuropeptide with Pleiotropic Roles

<i>p</i>-Synephrine: A Novel Agonist for Neuromedin U2 Receptor

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