Mice lacking bombesin receptor subtype-3 develop metabolic defects and obesity (original) (raw)

Nature volume 390, pages 165–169 (1997)Cite this article

Abstract

Mammalian bombesin-like peptides are widely distributed in the central nervous system as well as in the gastrointestinal tract, where they modulate smooth-muscle contraction, exocrine and endocrine processes, metabolism and behaviour1. They bind to G-protein-coupled receptors on the cell surface to elicit their effects. Bombesin-like peptide receptors cloned so far include, gastrin-releasing peptide receptor (GRP-R)2,3, neuromedin B receptor (NMB-R)4,5, and bombesin receptor subtype-3 (BRS-3)6,7. However, despite the molecular characterization of BRS-3, determination of its function has been difficult as a result of its low affinity for bombesin and its lack of an identified natural ligand. We have generated BRS-3-deficient mice in an attempt to determine the in vivo function of the receptor. Mice lacking functional BRS-3 developed a mild obesity, associated with hypertension and impairment of glucose metabolism. They also exhibited reduced metabolic rate, increased feeding efficiency and subsequent hyperphagia. Our data suggest that BRS-3 is required for the regulation of endocrine processes and metabolism responsible for energy balance and adiposity. BRS-3-deficient mice provide a useful new model for the investigation of human obesity and associated diseases.

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

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

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

Additional access options:

Similar content being viewed by others

References

  1. Lebacq-Verheyden, A.-M., Trepel, J., Sausville, E. A. & Battey, J. in Handbook of Experimental Pharmacology, Vol. 95/II. Peptide Growth Factors and their Receptors II (eds Sporn, M. B. &Roberts, A. B.) 71–124 (Springer, Berlin, Heidelberg, (1990)).
    Book Google Scholar
  2. Spindel, E. R., Giladi, E., Brehm, P., Goodman, R. H. & Segerson, T. P. Cloning and functional characterization of a complementary DNA encoding the murine fibroblast bombesin/gastrin-releasing peptide receptor. Mol. Endocrinol. 4, 1956–1963 (1990).
    Article CAS Google Scholar
  3. Battey, J. F. et al. Molecular cloning of the bombesin/gastrin-releasing peptide receptor from Swiss 3T3 cells. Proc. Natl Acad. Sci. USA 88, 395–399 (1991).
    Article ADS CAS Google Scholar
  4. Corjay, M. H. et al. Two distinct bombesin receptor subtypes are expressed and functional in human lung carcinoma cells. J. Biol. Chem. 266, 18771–18779 (1991).
    CAS PubMed Google Scholar
  5. Wada, E. et al. cDNA cloning, characterization, and brain region-specific expression of a neuromedin-B-preferring bombesin receptor. Neuron 6, 421–430 (1991).
    Article CAS Google Scholar
  6. Fathi, Z. et al. Anovel bombesin receptor subtype selectively expressed in testis and lung carcinoma cells. J. Biol. Chem. 268, 5979–5984 (1993).
    CAS PubMed Google Scholar
  7. Gorbulev, V., Akhundova, A., Buchner, H. & Fahrenholz, F. Molecular cloning of a new bombesin receptor subtype expressed in uterus during pregnancy. Eur. J. Biochem. 208, 405–410 (1992).
    Article CAS Google Scholar
  8. Ohki-Hamazaki, H., Wada, E., Matsui, K. & Wada, K. Cloning and expression of the neuromedin B receptor and the third subtype of bombesin receptor genes in the mouse. Brain Res. 762, 165–172 (1997).
    Article CAS Google Scholar
  9. Bray, G. A. & York, D. A. Hypothalamic and genetic obesity in experimental animals: An autonomic and endocrine hypothesis. Physiol. Rev. 59, 719–809 (1979).
    Article CAS Google Scholar
  10. Frederich, R. C. et al. Leptin levels reflect body lipid content in mice: Evidence for diet-induced resistance to leptin action. Nature Med. 1, 1311–1314 (1995).
    Article CAS Google Scholar
  11. Maffei, M. et al. Leptin levels in human and rodent: Measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nature Med. 1, 1155–1161 (1995).
    Article CAS Google Scholar
  12. Schwartz, M. W., Peskind, E., Raskind, M., Boyko, E. J. & Porte, D. J Cerebrospinal fluid leptin levels: Relationship to plasma levels and to adiposity in humans. Nature Med. 2, 589–593 (1996).
    Article CAS Google Scholar
  13. Wu, J. M., Nitecki, D. E., Biancalana, S. & Feldman, R. I. Discovery of high affinity bombesin receptor subtype 3 agonists. Mol. Pharmacol. 50, 1355–1363 (1996).
    CAS PubMed Google Scholar
  14. Boer, P. H. et al. Polymorphisms in the coding and noncoding region of murine _Pgk_-1 alleles. Biochem. Gen. 28, 299–308 (1990).
    Article CAS Google Scholar
  15. Yanofsky, R. L., Fine, M. & Pellow, J. W. Amutant neomycin phosphotransferase II gene reduces the resistance of transformants to antibiotic selection pressure. Proc. Natl Acad. Sci. USA 87, 3435–3439 (1990).
    Article ADS Google Scholar
  16. Nabeshima, Y. et al. Myogenin gene disruption results in perinatal lethality because of severe muscle defect. Nature 364, 532–535 (1993).
    Article ADS CAS Google Scholar
  17. Hooper, M., Hardy, K., Handyside, A., Hunter, S. & Monk, M. HPRT-deficient (Lesch–Nyhan) mouse embryos derived from germline colonization by cultured cells. Nature 326, 292–295 (1987).
    Article ADS CAS Google Scholar
  18. Yamamoto, K. & Kikuyama, S. Radioimmunoassay of prolactin in plasma of bullfrog tadpoles. Endocrinol. Jpn 29, 159–167 (1982).
    Article CAS Google Scholar
  19. Bouillaud, F., Weissenbach, J. & Ricquier, D. Complete cDNA-derived amino acid sequence of rat brown fat uncoupling protein. J. Biol. Chem. 261, 1487–1490 (1986).
    CAS PubMed Google Scholar

Download references

Acknowledgements

We thank J.-I. Miyazaki for ES cells and training regarding ES cells; A. F. Parlow for mouse growth hormone and polyclonal monkey anti-rat GH serum; K. Wakabayashi for goat anti-monkey IgG serum; H. Ohno for rat UCP1 probe; T. Nishikawa for providing Animex Auto; N. M. Le Douarin, K. Mikoshiba, R. S. Petralia and J. Smith for critical reading of the manuscript. This work was supported in part by research grants from the Ministry of Education, Science, Sports and Culture, the Ministry of Health and Welfare, the Science and Technology Agency of Japan, the Japan Health Science Foundation.

Author information

Authors and Affiliations

  1. Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, 187, Tokyo, Japan
    Hiroko Ohki-Hamazaki, Kei Watase, Kazuyuki Yamada, Hiroshi Maeno, Etsuko Wada & Keiji Wada
  2. Department of Neurochemistry, Tokyo Institute of Psychiatry, Setagaya, 156, Tokyo, Japan
    Hiroko Ohki-Hamazaki
  3. Department of Biology, School of Education, Waseda University, Shinjuku, 169-50, Tokyo, Japan
    Kazutoshi Yamamoto & Sakae Kikuyama
  4. Tsukuba Research Laboratories, Eisai Co. Ltd., Tsukuba, 300-26, Ibaraki, Japan
    Hiroo Ogura
  5. Osaka Prefectural College of Health Sciences, Habikino, 583, Osaka, Japan
    Mariko Yamano
  6. Department of Anatomy, Nippon Medical School, Bunkyo, Japan, 113, Tokyo
    Junko Imaki

Authors

  1. Hiroko Ohki-Hamazaki
    You can also search for this author inPubMed Google Scholar
  2. Kei Watase
    You can also search for this author inPubMed Google Scholar
  3. Kazutoshi Yamamoto
    You can also search for this author inPubMed Google Scholar
  4. Hiroo Ogura
    You can also search for this author inPubMed Google Scholar
  5. Mariko Yamano
    You can also search for this author inPubMed Google Scholar
  6. Kazuyuki Yamada
    You can also search for this author inPubMed Google Scholar
  7. Hiroshi Maeno
    You can also search for this author inPubMed Google Scholar
  8. Junko Imaki
    You can also search for this author inPubMed Google Scholar
  9. Sakae Kikuyama
    You can also search for this author inPubMed Google Scholar
  10. Etsuko Wada
    You can also search for this author inPubMed Google Scholar
  11. Keiji Wada
    You can also search for this author inPubMed Google Scholar

Corresponding authors

Correspondence toHiroko Ohki-Hamazaki or Keiji Wada.

Rights and permissions

About this article

Cite this article

Ohki-Hamazaki, H., Watase, K., Yamamoto, K. et al. Mice lacking bombesin receptor subtype-3 develop metabolic defects and obesity.Nature 390, 165–169 (1997). https://doi.org/10.1038/36568

Download citation

This article is cited by