Regulation of motivation for food by neuromedin U in the paraventricular nucleus and the dorsal raphe nucleus

McCue, David; Kasper, James M.; Hommel, Jonathan D.

doi:10.1038/ijo.2016.178

Cited by 30 publications

(23 citation statements)

References 57 publications

(79 reference statements)

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“…Most NMU studies, including ours, have been performed secondarily to intracerebral or peripheral administrations of NMU or stable forms of NMU (7, 11, 15, 22, 29, 30). However, the physiology of NMU secretion in the plasma is still unknown.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…That is, knockdown of NMUR2 in the paraventricular nucleus of the hypothalamus potentiates binge‐type eating, increases consumption of a high‐fat diet, and stimulates weight gain . Recent studies have also shown that NMU administered to the paraventricular nucleus of the hypothalamus also decreases intake and motivation for high‐fat diet . Taken together, NMUR2 activation shows therapeutic promise for treating obesity.…”

Section: Introductionmentioning

confidence: 97%

“…19 Recent studies have also shown that NMU administered to the paraventricular nucleus of the hypothalamus also decreases intake 20 and motivation for highfat diet. 5 Taken together, NMUR2 activation shows therapeutic promise for treating obesity.…”

Section: Introductionmentioning

confidence: 98%

“…Our objective is to identify and validate new druggable targets via pharmacological approaches that exploit an enhanced understanding of mechanisms underlying feeding behavior. Neuromedin U (NMU) is a neuropeptide, synthesized in the lateral hypothalamus and expressed in all mammals . NMU‐deficient mice are hyperphagic, obese, and have decreased metabolic activity .…”

Section: Introductionmentioning

confidence: 99%

“…Neuromedin U (NMU) is a neuropeptide, synthesized in the lateral hypothalamus and expressed in all mammals. 5 NMU-deficient mice are hyperphagic, obese, and have decreased metabolic activity. 6 Conversely, systemic administration of NMU peptide suppresses food intake 7 and causes weight loss.…”

Section: Introductionmentioning

confidence: 99%

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Small‐Molecule Neuromedin U Receptor 2 Agonists Suppress Food Intake and Decrease Visceral Fat in Animal Models

Sampson

Kasper

Felsing

et al. 2018

Pharmacology Res & Perspec

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Obesity is a growing public health concern, with 37.5% of the adult population in need of therapeutics that are more efficacious with a better side effect profile. An innovative target in this regard is neuromedin U, a neuropeptide shown to suppress food intake and attenuate weight gain in animal models. These effects of neuromedin U on feeding behavior are thought to be related to agonism at the centrally expressed neuromedin U receptor 2 (NMUR2). As peptides present unique challenges that limit their therapeutic potential, the discovery of small‐molecule NMUR2 agonists is needed to validate the targets therapeutic value, but to date, none have been evaluated in any animal model of disease. We therefore assessed two small‐molecule NMUR2 agonists for their in vitro signaling and their in vivo efficacy. The NMUR2 agonists were synthesized and both NMUR2 agonists, NY0116 and NY0128, decreased cAMP while stimulating calcium signaling in stably expressing NMUR2 HEK293 cells. When small‐molecule NMUR2 agonists were tested in vivo, acute administration significantly decreased high‐fat diet consumption. Repeated administration of the compounds decreased body weight and more specifically, decreased the percentage of visceral adipose tissue (VAT) in obese mice. These results have confirmed small‐molecule NMUR2 agonists are efficacious in animal models to decrease fat content, food intake, and body weight, suggesting NMUR2 is a promising therapeutic target for metabolic disorders.

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Pharmacomodulation of brain neuromedin U signaling as a potential therapeutic strategy

Pałasz

Worthington

Filipczyk

et al. 2023

J of Neuroscience Research

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Neuromedin U (NMU) belongs to a family of multifunctional neuropeptides that modulate the activity of several neural networks of the brain. Acting via metabotropic receptor NMUR2, NMU plays a role in the regulation of multiple systems, including energy homeostasis, stress responses, circadian rhythms, and endocrine signaling. The involvement of NMU signaling in the central regulation of important neurophysiological processes and its disturbances is a potential target for pharmacological modulation. Number of preclinical studies have proven that both modified NMU analogues such as PASR8‐NMU or F4R8‐NMU and designed NMUR2 agonists, for example, CPN‐116, CPN‐124 exhibit a distinct pharmacological activity especially when delivered transnasally. Their application can potentially be useful in the more convenient and safe treatment of obesity, eating disorders, Alzheimer's disease‐related memory impairment, alcohol addiction, and sleep disturbances. Accumulating findings suggest that pharmacomodulation of the central NMU signaling may be a promising strategy in the treatment of several neuropsychiatric disorders.

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Regulation of motivation for food by neuromedin U in the paraventricular nucleus and the dorsal raphe nucleus

Cited by 30 publications

References 57 publications

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

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

Small‐Molecule Neuromedin U Receptor 2 Agonists Suppress Food Intake and Decrease Visceral Fat in Animal Models

Pharmacomodulation of brain neuromedin U signaling as a potential therapeutic strategy

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