Association between Neuromedin U Gene Variants and Overweight and Obesity

Hainerová, Irena Aldhoon; Torekov, Signe S.; Ek, Jakob; Finková, Marie; Borch‐Johnsen, Knut; Jørgensen, Torben; Madsen, Ole; Lebl, Jan; Hansen, Torben; Pedersen, Oluf

doi:10.1210/jc.2006-1442

Cited by 56 publications

(33 citation statements)

References 18 publications

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“…NMU-25 potently suppressed glucose-stimulated insulin secretion from human islets in static batch culture assays (Figure 7H, P < 0.001 for GSIS) and islet perifusion experiments (Figure 7I–K). An NMU R165W allele that encodes a mutant peptide was previously found to co-segregate in an autosomal dominant pattern with early-onset obesity (Hainerová et al 2006). In that study, a subset of carriers displayed elevated insulin C-peptide levels; based on these findings and mutation of the highly conserved NMU C-terminal pentapeptide in this family, we reasoned that suppression of insulin secretion might be impaired by the mutant NMU R165W variant.…”

Section: Resultsmentioning

confidence: 99%

Suppression of Insulin Production and Secretion by a Decretin Hormone

et al. 2015

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SUMMARY Decretins, hormones induced by fasting that suppress insulin production and secretion, have been postulated from classical human metabolic studies. From genetic screens, we identified Drosophila Limostatin (Lst), a peptide hormone that suppresses insulin secretion. Lst is induced by nutrient restriction in gut-associated endocrine cells. limostatin deficiency led to hyperinsulinemia, hypoglycemia and excess adiposity. A conserved 15-residue polypeptide encoded by limostatin suppressed secretion by insulin-producing cells. Targeted knockdown of CG9918, a Drosophila orthologue of Neuromedin U receptors (NMUR), in insulin-producing cells phenocopied limostatin deficiency, and attenuated insulin suppression by purified Lst, suggesting CG9918 encodes an Lst receptor. NMUR1 is expressed in islet β-cells, and purified NMU suppresses insulin secretion from human islets. A human mutant NMU variant that co-segregates with familial early-onset obesity and hyperinsulinemia fails to suppress insulin secretion. We propose Lst as an index member of an ancient hormone class called decretins, which suppress insulin output.

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Section: Resultsmentioning

confidence: 99%

Suppression of Insulin Production and Secretion by a Decretin Hormone

et al. 2015

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“…NmU reduced their fat mass (73 ), and transgenic mice overexpressing NmU displayed reduced body weight and fat storage compared to their wild-type littermates, even on a high-fat diet (86 ). Moreover, certain genetic variants of NmU-which according to structure/function correlation appear to be devoid of or have reduced functional activity-are associated with overweight and obesity (87 ). NmU expression appears to be regulated by feeding behavior as well, because NmU concentrations in the hypothalamus are reduced by fasting (36 ).…”

Section: Energy Homeostasis and Feedingmentioning

confidence: 99%

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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“…Some have found that mice lacking the NMUR2 gene do not show this phenotype (218), but others have found that NMUR2-deficient mice are lean, hypophagic, and somewhat resistant to weight and fat gain on a high-fat diet (190). In humans, variants in the gene encoding pro-NMU are associated with obesity (219). This led to interest in neuromedins as a potential target for weight-loss therapy.…”

Section: Neuromedinsmentioning

confidence: 99%

Neuropeptides Controlling Energy Balance: Orexins and Neuromedins

Nixon

Kotz

Novak

et al. 2011

Handbook of Experimental Pharmacology

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In this section we review the feeding and energy expenditure effects of orexin (also known as hypocretin) and neuromedin. Orexins are multifunctional neuropeptides that affect energy balance by participating in regulation of appetite, arousal, and spontaneous physical activity. Central orexin signaling for all functions originates in the lateral hypothalamus–perifornical area, and is likely functionally differentiated based on site of action and on interacting neural influences. The effect of orexin on feeding is likely related to arousal in some ways, but is nonetheless a separate neural process that depends on interactions with other feeding related neuropeptides. In a pattern distinct from other neuropeptides, orexin stimulates both feeding and energy expenditure. Orexin increases in energy expenditure are mainly by increasing spontaneous physical activity, and this energy expenditure effect is more potent than the effect on feeding. Global orexin manipulations, such as in transgenic models, produce energy balance changes consistent with a dominant energy expenditure effect of orexin. Neuromedins are gut-brain peptides that reduce appetite. There are gut sources of neuromedin, but likely the key appetite related neuromedin producing neurons are in hypothalamus and parallel other key anorectic neuropeptide expression in the arcuate to paraventricular hypothalamic projection. As with other hypothalamic feeding related peptides, hindbrain sites are likely also important sources and targets of neuromedin anorectic action. Neuromedin increases physical activity in addition to reducing appetite, thus producing a consistent negative energy balance effect. Together with the various other neuro-peptides, -transmitters, -modulators and –hormones, neuromedin and orexin act in the appetite network to produce changes in food intake and energy expenditure, which ultimately influences the regulation of body weight.

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Association between Neuromedin U Gene Variants and Overweight and Obesity

Abstract: Amino acid variants in NMU associate with overweight and obesity, suggesting that NMU is involved in energy regulation in humans.

Cited by 56 publications

References 18 publications

Suppression of Insulin Production and Secretion by a Decretin Hormone

Suppression of Insulin Production and Secretion by a Decretin Hormone

Neuromedin U: A Multifunctional Neuropeptide with Pleiotropic Roles

Neuropeptides Controlling Energy Balance: Orexins and Neuromedins

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