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Appetite-modifying actions of pro-neuromedin U-derived peptides.

Bechtold DA, Ivanov TR, Luckman SM - Am. J. Physiol. Endocrinol. Metab. (2009)

Bottom Line: Neuromedin U (NMU) is known to have potent actions on appetite and energy expenditure.Here, we show that central administration of NMU or the related peptide neuromedin S (NMS) dose-dependently decreases food intake, increases metabolic rate, and leads to significant weight loss in mice.Specifically, central administration of proNMU(104-136) causes a significant but transient ( approximately 4 h) increase in feeding, yet both food intake and body weight are decreased over the following 24 h. proNMU(104-136) administration also significantly increased metabolic rate.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.

ABSTRACT
Neuromedin U (NMU) is known to have potent actions on appetite and energy expenditure. Deletion of the NMU gene in mice leads to an obese phenotype, characterized by hyperphagia and decreased energy expenditure. Conversely, transgenic mice that overexpress proNMU exhibit reduced body weight and fat storage. Here, we show that central administration of NMU or the related peptide neuromedin S (NMS) dose-dependently decreases food intake, increases metabolic rate, and leads to significant weight loss in mice. The effects of NMU and NMS on both feeding and metabolism are almost completely lost in mice lacking the putative CNS receptor for NMU and NMS, NMUr2. However, NMUr2 knockout mice do not exhibit overt differences in body weight or energy expenditure compared with wild-type mice, suggesting that the dramatic phenotype of the NMU gene knockout mouse is not due simply to the loss of NMU/NMUr2 signaling. Putative proteolytic cleavage sites indicate that an additional peptide is produced from the NMU precursor protein, which is extremely well conserved between human, mouse, and rat. Here, we demonstrate that this peptide, proNMU(104-136), has a pronounced effect on energy balance in mice. Specifically, central administration of proNMU(104-136) causes a significant but transient ( approximately 4 h) increase in feeding, yet both food intake and body weight are decreased over the following 24 h. proNMU(104-136) administration also significantly increased metabolic rate. These results suggest that proNMU(104-136) is a novel modulator of energy balance and may contribute to the phenotype exhibited by NMU knockout mice.

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proNMU104-136-induced c-Fos expression. Representative photomicrographs of c-Fos immunoreactivity in mice treated with vehicle (right) or and proNMU104-136 (left) 90 min postinjection. Increased c-Fos immunoreactive profiles were observed in the PVN (A), DMN (B), central amygdala (C), and the lining of the 3rd ventricle (A–B) proNMU104-136 administration. Within the medulla, intense c-Fos expression was observed in the NTS (D) and inferior olive (E) of peptide-treated mice. No significant increases in c-Fos expression were observed in the arcuate, ventormedial, or lateral hypothalamus, locus coeruleus, or parabrachial nucleus; n = 5 mice/group.
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f4: proNMU104-136-induced c-Fos expression. Representative photomicrographs of c-Fos immunoreactivity in mice treated with vehicle (right) or and proNMU104-136 (left) 90 min postinjection. Increased c-Fos immunoreactive profiles were observed in the PVN (A), DMN (B), central amygdala (C), and the lining of the 3rd ventricle (A–B) proNMU104-136 administration. Within the medulla, intense c-Fos expression was observed in the NTS (D) and inferior olive (E) of peptide-treated mice. No significant increases in c-Fos expression were observed in the arcuate, ventormedial, or lateral hypothalamus, locus coeruleus, or parabrachial nucleus; n = 5 mice/group.

Mentions: To explore the possibility that additional peptide products of the NMU gene also influence energy balance, proNMU104-136 was administered to mice. In contrast to NMU and NMS, central administration of proNMU104-136 (0.5–2 nmol) at the start of the night (ZT12) increased feeding over the short term (Fig. 3A, 1 h). The short-term orexigenic effects of proNMU104-136 were accentuated (relative to controls) when the peptide was administered to mice at ZT2, outside their normal feeding time (Fig. 3C). Nonetheless, proNMU104-136 administration ultimately reduced cumulative food intake over 24 h postinjection (Fig. 3A), which was accompanied by a significant loss in body weight (Fig. 3B). Body weight loss was similar in magnitude to that observed following NMU administration. In line with the reduction in body weight, proNMU104-136 administration caused a significant increase in V̇o2that was sustained over 24 h postinjection (Fig. 3, D and E). Short-term orexigenic effects of proNMU104-136 on food intake were maintained in NMUr2−/− mice, although no decrease in food intake was observed 24 h after injection in these mice (Fig. 3F; n = 5–6 mice/group, ZT2). Nevertheless, proNMU104-136 administration reduced body weight (Fig. 4G) and elevated metabolic rate (Fig. 3H) in the NMUr2−/− mice.


Appetite-modifying actions of pro-neuromedin U-derived peptides.

Bechtold DA, Ivanov TR, Luckman SM - Am. J. Physiol. Endocrinol. Metab. (2009)

proNMU104-136-induced c-Fos expression. Representative photomicrographs of c-Fos immunoreactivity in mice treated with vehicle (right) or and proNMU104-136 (left) 90 min postinjection. Increased c-Fos immunoreactive profiles were observed in the PVN (A), DMN (B), central amygdala (C), and the lining of the 3rd ventricle (A–B) proNMU104-136 administration. Within the medulla, intense c-Fos expression was observed in the NTS (D) and inferior olive (E) of peptide-treated mice. No significant increases in c-Fos expression were observed in the arcuate, ventormedial, or lateral hypothalamus, locus coeruleus, or parabrachial nucleus; n = 5 mice/group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2724114&req=5

f4: proNMU104-136-induced c-Fos expression. Representative photomicrographs of c-Fos immunoreactivity in mice treated with vehicle (right) or and proNMU104-136 (left) 90 min postinjection. Increased c-Fos immunoreactive profiles were observed in the PVN (A), DMN (B), central amygdala (C), and the lining of the 3rd ventricle (A–B) proNMU104-136 administration. Within the medulla, intense c-Fos expression was observed in the NTS (D) and inferior olive (E) of peptide-treated mice. No significant increases in c-Fos expression were observed in the arcuate, ventormedial, or lateral hypothalamus, locus coeruleus, or parabrachial nucleus; n = 5 mice/group.
Mentions: To explore the possibility that additional peptide products of the NMU gene also influence energy balance, proNMU104-136 was administered to mice. In contrast to NMU and NMS, central administration of proNMU104-136 (0.5–2 nmol) at the start of the night (ZT12) increased feeding over the short term (Fig. 3A, 1 h). The short-term orexigenic effects of proNMU104-136 were accentuated (relative to controls) when the peptide was administered to mice at ZT2, outside their normal feeding time (Fig. 3C). Nonetheless, proNMU104-136 administration ultimately reduced cumulative food intake over 24 h postinjection (Fig. 3A), which was accompanied by a significant loss in body weight (Fig. 3B). Body weight loss was similar in magnitude to that observed following NMU administration. In line with the reduction in body weight, proNMU104-136 administration caused a significant increase in V̇o2that was sustained over 24 h postinjection (Fig. 3, D and E). Short-term orexigenic effects of proNMU104-136 on food intake were maintained in NMUr2−/− mice, although no decrease in food intake was observed 24 h after injection in these mice (Fig. 3F; n = 5–6 mice/group, ZT2). Nevertheless, proNMU104-136 administration reduced body weight (Fig. 4G) and elevated metabolic rate (Fig. 3H) in the NMUr2−/− mice.

Bottom Line: Neuromedin U (NMU) is known to have potent actions on appetite and energy expenditure.Here, we show that central administration of NMU or the related peptide neuromedin S (NMS) dose-dependently decreases food intake, increases metabolic rate, and leads to significant weight loss in mice.Specifically, central administration of proNMU(104-136) causes a significant but transient ( approximately 4 h) increase in feeding, yet both food intake and body weight are decreased over the following 24 h. proNMU(104-136) administration also significantly increased metabolic rate.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.

ABSTRACT
Neuromedin U (NMU) is known to have potent actions on appetite and energy expenditure. Deletion of the NMU gene in mice leads to an obese phenotype, characterized by hyperphagia and decreased energy expenditure. Conversely, transgenic mice that overexpress proNMU exhibit reduced body weight and fat storage. Here, we show that central administration of NMU or the related peptide neuromedin S (NMS) dose-dependently decreases food intake, increases metabolic rate, and leads to significant weight loss in mice. The effects of NMU and NMS on both feeding and metabolism are almost completely lost in mice lacking the putative CNS receptor for NMU and NMS, NMUr2. However, NMUr2 knockout mice do not exhibit overt differences in body weight or energy expenditure compared with wild-type mice, suggesting that the dramatic phenotype of the NMU gene knockout mouse is not due simply to the loss of NMU/NMUr2 signaling. Putative proteolytic cleavage sites indicate that an additional peptide is produced from the NMU precursor protein, which is extremely well conserved between human, mouse, and rat. Here, we demonstrate that this peptide, proNMU(104-136), has a pronounced effect on energy balance in mice. Specifically, central administration of proNMU(104-136) causes a significant but transient ( approximately 4 h) increase in feeding, yet both food intake and body weight are decreased over the following 24 h. proNMU(104-136) administration also significantly increased metabolic rate. These results suggest that proNMU(104-136) is a novel modulator of energy balance and may contribute to the phenotype exhibited by NMU knockout mice.

Show MeSH
Related in: MedlinePlus