Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Neuromedin U has a novel anorexigenic effect independent of the leptin signaling pathway

Nature Medicine volume 10, pages 1067–1073 (2004)Cite this article

Abstract

Neuromedin U (NMU) is a hypothalamic neuropeptide that regulates body weight and composition. Here we show that mice lacking the gene encoding NMU (Nmu−/− mice) develop obesity. Nmu−/− mice showed increased body weight and adiposity, hyperphagia, and decreased locomotor activity and energy expenditure. Obese Nmu−/− mice developed hyperleptinemia, hyperinsulinemia, late-onset hyperglycemia and hyperlipidemia. Notably, however, treatment with exogenous leptin was effective in reducing body weight in obese Nmu−/− mice. In addition, central leptin administration did not affect NMU gene expression in the hypothalamus of rats. These results indicate that NMU plays an important role in the regulation of feeding behavior and energy metabolism independent of the leptin signaling pathway. These characteristic functions of NMU may provide new insight for understanding the pathophysiological basis of obesity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Body weight, fat composition and histological analyses of male Nmu−/− and wild-type mice.
Figure 2: Feeding behavior, locomotor activity and basal oxygen consumption of Nmu−/− and wild-type mice at 24 weeks of age (n = 16).
Figure 3: Northern blot analysis of Ucp1 mRNA in BAT and Ucp 3 mRNA in skeletal muscle of Nmu−/− and wild-type mice at 24 weeks of age (n = 16).
Figure 4: Quantitative in situ hybridization and immunohistochemistry of Nmu−/− and wild-type mice, and NMU-administered rats.
Figure 5: Quantitative in situ hybridization in leptin administered rats (n = 6 per group).
Figure 6: Effect of leptin administration on Nmu−/− and wild-type (WT) mice at 24 weeks of age (n = 10).

Similar content being viewed by others

References

  1. Cummings, D.E. & Schwartz, M.W. Genetics and pathophysiology of human obesity. Annu. Rev. Med. 54, 453–471 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Marx, J. Cellular warriors at the battle of the bulge. Science 299, 846–849 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Kalra, S.P. et al. Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr. Rev. 20, 68–100 (1999).

    CAS  PubMed  Google Scholar 

  4. Minamino, N., Kangawa, K. & Matsuo, H. Neuromedin U-8 and U-25: novel uterus stimulating and hypertensive peptides identified in porcine spinal cord. Biochem. Biophys. Res. Commun. 130, 1078–1085 (1985).

    Article  CAS  PubMed  Google Scholar 

  5. Ballesta, J. et al. Occurrence and developmental pattern of neuromedin U-immunoreactive nerves in the gastrointestinal tract and brain of the rat. Neuroscience 25, 797–816 (1988).

    Article  CAS  PubMed  Google Scholar 

  6. Howard, A.D. et al. Identification of receptors for neuromedin U and its role in feeding. Nature 406, 70–74 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Graham, E.S. et al. Neuromedin U and Neuromedin U receptor-2 expression in the mouse and rat hypothalamus: effects of nutritional status. J. Neurochem. 87, 1165–1173 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Fujii, R. et al. Identification of neuromedin U as the cognate ligand of the orphan G protein-coupled receptor FM-3. J. Biol. Chem. 275, 21068–21074 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Kojima, M. et al. Purification and identification of neuromedin U as an endogenous ligand for an orphan receptor GPR66 (FM3). Biochem. Biophys. Res. Commun. 276, 435–438 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Nakazato, M. et al. Central effects of neuromedin U in the regulation of energy homeostasis. Biochem. Biophys. Res. Commun. 277, 191–194 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Hanada, R. et al. A role for neuromedin U in stress response. Biochem. Biophys. Res. Commun. 289, 225–228 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Nakahara, K. et al. The gut-brain peptide neuromedin U is involved in the mammalian circadian oscillator system. Biochem. Biophys. Res. Commun. 318, 156–161 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Campfield, L.A., Smith, F.J., Guisez, Y., Devos, R. & Burn, P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269, 546–549 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Pelleymounter, M.A. et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269, 540–543 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Schwartz, M.W., Seeley, R.J., Campfield, L.A., Burn, P. & Baskin, D.G. Identification of targets of leptin action in rat hypothalamus. J. Clin. Invest. 98, 1101–1106 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Robinson, S.W., Dinulescu, D.M. & Cone, R.D. Genetic models of obesity and energy balance in the mouse. Annu. Rev. Genet. 34, 687–745 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Kurokawa, M., Akino, K. & Kanda, K. A new apparatus for studying feeding and drinking in the mouse. Physiol. Behav. 70, 105–112 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Nicholls, D.G. A history of UCP1. Biochem. Soc. Trans. 29, 751–755 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Masaki, T. et al. Corticotropin-releasing hormone-mediated pathway of leptin to regulate feeding, adiposity, and uncoupling protein expression in mice. Endocrinology 144, 3547–3554 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Schrauwen, P. & Hesselink, M. Uncoupling protein 3 and physical activity: the role of uncoupling protein 3 in energy metabolism revisited. Proc. Nutr. Soc. 62, 635–643 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Vidal-Puig, A.J. et al. Energy metabolism in uncoupling protein 3 gene knockout mice. J. Biol. Chem. 275, 16258–16266 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Fan, W., Boston, B.A., Kesterson, R.A., Hruby, V.J. & Cone, R.D. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385, 165–168 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Abbott, C.R. et al. Investigation of the melanocyte stimulating hormones on food intake. Lack Of evidence to support a role for the melanocortin-3-receptor. Brain. Res. 869, 203–210 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Moussa, N.M. & Claycombe, K.J. The yellow mouse obesity syndrome and mechanisms of agouti-induced obesity. Obes. Res. 7, 506–514 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Egawa, M., Yoshimatsu, H. & Bray, G.A. Effect of corticotropin releasing hormone and neuropeptide Y on electrophysiological activity of sympathetic nerves to interscapular brown adipose tissue. Neuroscience 34, 771–775 (1990).

    Article  CAS  PubMed  Google Scholar 

  27. Ivanov, T.R., Lawrence, C.B., Stanley, P.J. & Luckman, S.M. Evaluation of neuromedin U actions in energy homeostasis and pituitary function. Endocrinology 143, 3813–3821 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Ozaki, Y. et al. Centrally administered neuromedin U activates neurosecretion and induction of c-fos messenger ribonucleic acid in the paraventricular and supraoptic nuclei of rat. Endocrinology 143, 4320–4329 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Hanada, T. et al. Central actions of neuromedin U via corticotropin-releasing hormone. Biochem. Biophys. Res. Commun. 311, 954–958 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Wren, A.M. et al. Hypothalamic actions of neuromedin U. Endocrinology 143, 4227–4234 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Schwartz, M.W. et al. Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 46, 2119–2123 (1997).

    Article  CAS  PubMed  Google Scholar 

  32. Mizuno, T.M. & Mobbs, C.V. Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting. Endocrinology 140, 814–817 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Elmquist, J.K. & Flier, J.S. Neuroscience. The fat-brain axis enters a new dimension. Science 304, 63–64 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Schwartz, M.W., Peskind, E., Raskind, M., Boyko, E.J. & Porte, D., Jr. Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat. Med. 2, 589–593 (1996).

    Article  CAS  PubMed  Google Scholar 

  35. Caro, J.F. et al. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 348, 159–161 (1996).

    Article  CAS  PubMed  Google Scholar 

  36. Friedman, J.M. & Halaas, J.L. Leptin and the regulation of body weight in mammals. Nature 395, 763–770 (1998).

    Article  CAS  PubMed  Google Scholar 

  37. Masaki, T., Yoshimatsu, H., Chiba, S., Watanabe, T. & Sakata, T. Central infusion of histamine reduces fat accumulation and upregulates UCP family in leptin-resistant obese mice. Diabetes 50, 376–384 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Withers, P.C. Measurement of VO2, VCO2, and evaporative water loss with a flow-through mask. J. Appl. Physiol. 42, 120–123 (1977).

    Article  CAS  PubMed  Google Scholar 

  39. Yamamoto, Y., Ueta, Y., Yamashita, H., Asayama, K. & Shirahata, A. Expressions of the prepro-orexin and orexin type 2 receptor genes in obese rat. Peptides 23, 1689–1696 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Nomura, M. et al. Enhanced up-regulation of corticotropin-releasing hormone gene expression in response to restraint stress in the hypothalamic paraventricular nucleus of oxytocin gene-deficient male mice. J. Neuroendocrinol. 15, 1054–1061 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Yamamoto, Y. et al. Effects of food restriction on the hypothalamic prepro-orexin gene expression in genetically obese mice. Brain. Res. Bull. 51, 515–521 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Isse, T. et al. Effects of leptin on fasting-induced inhibition of neuronal nitric oxide synthase mRNA in the paraventricular and supraoptic nuclei of rats. Brain. Res. 846, 229–235 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Hanada, R. et al. Differential regulation of melanin-concentrating hormone and orexin genes in the agouti-related protein/melanocortin-4 receptor system. Biochem. Biophys. Res. Commun. 268, 88–91 (2000).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Y. Yamashita, Y. Maruyama, M. Minamino, M. Miyazato, K. Mori, Y. Date, M. Nakazato, H. Ohgusu, M. Naitou, A. Yoshimura and D. Marini for their assistance. This work was supported by the Program for Promotion of Basic Research Activities for Innovative Biosciences (PROBRAIN) (to M.K.), the Fujisawa Foundation, Takeda Science Foundation, Brain Science Foundation, the Naito Foundation and the Mitsubishi Foundation (to M.K.). This work was also supported in part by the Program for Promotion of Fundamental Studies in Health Sciences of Pharmaceuticals and Medical Devices Agency (PMDA) of Japan (to K.K.), and Grant-in-Aids for Scientific Research (S) (to K.K.) (B) (to M.K.), and Young Scientists (B) (to R.H.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Author information

Authors and Affiliations

  1. Molecular Genetics, Institute of Life Science, Kurume University, Kurume, 839-0861, Fukuoka, Japan

    Reiko Hanada, Hitoshi Teranishi, Nobuhiro Fukushima, Yoshihiko Fukue & Masayasu Kojima

  2. Department of Internal Medicine, Faculty of Medicine, Oita University, Oita, 879-5593, Japan

    Reiko Hanada & Hironobu Yoshimatsu

  3. Department of Cardiac Physiology, National Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, 565-8565, Osaka, Japan

    James Todd Pearson & Mikiyasu Shirai

  4. Department of Anatomy, Nagasaki University, School of Medicine, Nagasaki, 852-8523, Japan

    Mamoru Kurokawa

  5. Department of Biochemistry, National Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, 565-8565, Osaka, Japan

    Hiroshi Hosoda & Kenji Kangawa

  6. Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyusyu, 807-8555, Japan

    Ryota Serino, Hiroaki Fujihara & Yoichi Ueta

  7. Department of Experimental Genome Research, Genome Information Research Center, Osaka University, Yamadaoka 3-1, Suita, 565-0871, Osaka, Japan

    Masahito Ikawa & Masaru Okabe

  8. Department of Veterinary Physiology, Faculty of Agriculture, Miyazaki University, Miyazaki, 889-2155, Japan

    Noboru Murakami

Authors
  1. Reiko Hanada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hitoshi Teranishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James Todd Pearson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mamoru Kurokawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroshi Hosoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nobuhiro Fukushima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshihiko Fukue
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ryota Serino
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hiroaki Fujihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yoichi Ueta
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Masahito Ikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Masaru Okabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Noboru Murakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Mikiyasu Shirai
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Hironobu Yoshimatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Kenji Kangawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Masayasu Kojima
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masayasu Kojima.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Generation of NMU−/− mice. (PDF 98 kb)

Supplementary Fig. 2

Plasma levels of glucose, insulin, leptin, lipids, corticosterone and assessment of thyroid function in NMU−/− and WT mice after a 16-hr starvation period (n = 16). (PDF 36 kb)

Supplementary Fig. 3

Circadian phenotypes of feeding behavior in NMU−/− mice and WT mouse. (PDF 55 kb)

Supplementary Fig. 4

Suppression of food intake by bolus ICV administration of NMU (3 nmol/mouse or 5nmol/rat) in animals without leptin signaling after fasting (n = 6 per group). (PDF 30 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hanada, R., Teranishi, H., Pearson, J. et al. Neuromedin U has a novel anorexigenic effect independent of the leptin signaling pathway. Nat Med 10, 1067–1073 (2004). https://doi.org/10.1038/nm1106

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1106

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing