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Cited by 12Regulation of Appetite and ObesityNeuropeptides and Animal PhysiologyHypothalamic control of reproductive hormones

Neuromedin S and U

Open access
Novak, Colleen M.·2009·Endocrinology
DOI 10.1210/en.2009-0448PMC PMC2703548
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Abstract

The physiological and endocrine homeostatic systems that regulate body weight are complex. Several peripheral systems need to be coordinated with central nervous system processes for proper energy balance regulation. Systems for energy storage (white adipose tissue), energy expenditure (skeletal muscle and brown adipose tissue), and energy absorption (gut) (1) inform the brain how much fuel is available short- and long-term. These systems coordinate with expected fuel demand, which is impacted by environment, temperature, season, reproduction and offspring care, food availability, and predation pressure. Whereas a handful of mainstream peptides receive ample of attention from investigators, other important signals are less recognized. A recent study by Peier et al. (2) highlights the importance of neuromedins U (NMU) and S (NMS) acting centrally on the NMU receptor 2 (NMUR2) in the regulation of body weight homeostasis. So what are these neuromedins and why do they matter? NMU, first described in 1985 and named for its ability to stimulate smooth muscle contraction in the uterus (3), is a peptide synthesized in and secreted from several tissues, most notably (for our purposes), the gut and the brain (4) (Fig. 1). NMU acts on the brain to dampen energy intake and increase energy expenditure, partially through heightened physical activity (5, 6, 7, 8, 9). Thus, NMU follows a common pattern seen in hormones related to energy balance (10). Although NMU is found in the gut and stimulates smooth muscle contraction there (4), there is little evidence to suggest that it is released into the general circulation to act on the brain. Instead, it may be one mechanism through which leptin acts to exert its effects on energy balance and behavior (8, 11, 12). Also found in the brain is NMS, which is structurally similar to although not, as the authors point out, a splice variant of NMU (2, 13, 14). The S in NMS stands for the suprachiasmatic nucleus (SCN), the primary circadian clock in mammals or, as many circadian biologists consider it to be, the seat of the soul (take that, pineal gland). The precise nuclear locations of NMU and NMS within the brain are somewhat disputed because their sequence and structural similarities make interpretation of binding specificity problematic, but it is safe to say that NMU is synthesized in hypothalamic nuclei that are critical players in regulating energy homeostasis, and NMS is found predominantly in the SCN (13, 14, 15, 16, 17). A generalized schematic of the role of NMU and NMS in energy balance regulation. NMU is made in peripheral tissues, including the small intestine, but there is little evidence that it is released into the general circulation (4 ). Evidence suggests that circulating leptin induces NMU release (although NMU is not the only route through which leptin induces its central effects) (8, 11, 12 ). NMU is synthesized in hypothalamic brain regions important in energy balance regulation, and NMS is found in the SCN, the primary circadian clock in mammals (13–16, 33, 34 ). They both act centrally, primarily through the NMUR2, to decrease food intake and increase energy expenditure. This results in weight loss. One take-home message from Peier et al. (2) is that chronic centrally applied NMU and NMS can decrease food intake and body weight (and, for NMU, alter body temperature) over 2 wk. The apparent potency did not diminish over time. Along with other studies, this hints that there may be individual differences in the NMU system that could be associated with obesity (18, 19). Others, however, found that serial intra-paraventricular nucleus intraparaventricular (PVN) injections of NMU did not significantly alter body weight (20). Different methods and models can yield different results, but the data in Peier et al. were consistent: NMU and NMS induced weight loss in more than one study and mouse genotype. That these findings are inconsistent with previously reported results may suggest that whereas the PVN may play a role in NMU-induced physical activity and energy expenditure (5, 6), other brain regions may be more important in the effects seen in the study by Peier et al. (2), who infused NMU intracerebroventricularly. These two peptides, NMU and NMS, act on the same two receptors. As an oversimplification, NMUR1 is found in the predominantly in the periphery, and NMUR2 is found mostly in the brain (4, 9, 15, 21, 22). Here, the authors focus specifically the role of NMUR2 in the central actions of NMU and NMS. This leads to the second take-home message: the acute and chronic effects of central NMU and NMS, for the most part, appear to depend on NMUR2. NMU and NMS did not have the same effects in mice deficient in NMUR2 compared with wild types (WT), whereas NMUR1−/− mice were very similar to WT mice in their response to chronic central NMU. The authors, combining genetic and pharmacological manipulations, make a convincing argument for an important physiological role

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  • eQTL, PheWAS, and model organism evidence support the hypothesis that introgressed alleles downregulate NMUR2 in the brain leading to increased morningness.

    “In the Supplemental Text, we describe eQTL, PheWAS, and model organism evidence supporting the hypothesis that introgressed alleles downregulate NMUR2 in the brain leading to increased morningness61–65.”

    From Quantifying the contribution of Neanderthal introgression to the heritability of complex traits (2021) · cites this paper as [63]

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Authors
Novak, C. M.
Affiliations
Mayo Clinic (US)
Corresponding author
Novak, Colleen M.
ORCID
Novak, Colleen M.
Venue
Endocrinology
Publisher
The Endocrine Society
Published
2009-07-01
Volume
150
Issue
7
Pages
2985-2987
ISSN
  • 0013-7227 (ISSN-L)
  • 1945-7170
DOI
10.1210/en.2009-0448
PMC
PMC2703548
OpenAlex
W2147351581
Cited by
12
References
34
Citations by year
2025: 2 · 2023: 1 · 2022: 1 · 2021: 1 · 2015: 2 · 2013: 1 · 2012: 1
FWCI
0.60
Type
journal article
Language
en
Open access
Locations
  • Endocrinology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Keywords
neuromedin S, neuromedin U, energy balance, body weight homeostasis, suprachiasmatic nucleus, circadian clock, hypothalamus, gut-brain signaling, leptin, gut peptides, appetite regulation, energy expenditure, brown adipose tissue, white adipose tissue, physical activity
MeSH terms
Animals, Energy Metabolism, Humans, Neuropeptides

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