Mice lacking bombesin receptor subtype-3 develop metabolic defects and obesity


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.

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Figure 1: Targeted disruption of the BRS-3 gene.
Figure 2: Intake of food and water and change in body weight in wild-type and BRS-3-deficient mice.
Figure 3: Oral glucose tolerance tests for wild-type and mutant mice.
Figure 4: Insulin tolerance tests for wild-type and mutant mice.
Figure 5: Measures of metabolic activity in wild-type and BRS-3-deficient mice.


  1. 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)).

    Google Scholar 

  2. 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).

    CAS  Article  Google Scholar 

  3. 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).

    ADS  CAS  Article  Google Scholar 

  4. 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. 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).

    CAS  Article  Google Scholar 

  6. 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. 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).

    CAS  Article  Google Scholar 

  8. 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).

    CAS  Article  Google Scholar 

  9. 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).

    CAS  Article  Google Scholar 

  10. 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).

    CAS  Article  Google Scholar 

  11. 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).

    CAS  Article  Google Scholar 

  12. 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).

    CAS  Article  Google Scholar 

  13. 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. 14

    Boer, P. H. et al. Polymorphisms in the coding and noncoding region of murine Pgk-1 alleles. Biochem. Gen. 28, 299–308 (1990).

    CAS  Article  Google Scholar 

  15. 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).

    ADS  Article  Google Scholar 

  16. 16

    Nabeshima, Y. et al. Myogenin gene disruption results in perinatal lethality because of severe muscle defect. Nature 364, 532–535 (1993).

    ADS  CAS  Article  Google Scholar 

  17. 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).

    ADS  CAS  Article  Google Scholar 

  18. 18

    Yamamoto, K. & Kikuyama, S. Radioimmunoassay of prolactin in plasma of bullfrog tadpoles. Endocrinol. Jpn 29, 159–167 (1982).

    CAS  Article  Google Scholar 

  19. 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 

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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.

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Correspondence to Hiroko Ohki-Hamazaki or Keiji Wada.

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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

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