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Role of melanocortinergic neurons in feeding and the agouti obesity syndrome

Abstract

DOMINANT alleles at the agouti locus (A) cause an obesity syndrome in the mouse, as a consequence of ectopic expression of the agouti peptide1–6. This peptide, normally only found in the skin, is a high-affinity antagonist of the melanocyte-stimulating hormone receptor (MC1-R)7, thus explaining the inhibitory effect of agouti on eumelanin pigment synthesis. The agouti peptide is also an antagonist of the hypothalamic melanocortin-4 receptor (MC4-R)7–9. To test the hypothesis that agouti causes obesity by antagonism of hypothalamic melanocortin receptors7, we identified cyclic melanocortin analogues10 that are potent agonists or antagonists of the neural MC3 (refs 11, 12) and MC4 receptors. Intracerebroventricular administration of the agonist, MTII, inhibited feeding in four models of hyperphagia: fasted C57BL/6J, ob/ob, and AY mice, and mice injected with neuropeptide Y. Co-administration of the specific melanocortin antagonist and agouti-mimetic SHU9119 completely blocked this inhibition. Furthermore, administration of SHU9119 significantly enhanced nocturnal feeding, or feeding stimulated by a prior fast. Our data show that melanocortinergic neurons exert a tonic inhibition of feeding behaviour. Chronic disruption of this inhibitory signal is a likely explanation of the agouti obesity syndrome.

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References

  1. Klebig, M. L., Wilkinson, J. E., Geisler, J. G. & Woychik, R. P. Proc. Natl Acad. Sci. USA 92, 4728–4732 (1995).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bultman, S. J., Michaud, E. J. & Woychik, R. P. Cell 71, 1195–1204 (1992).

    Article  CAS  PubMed  Google Scholar 

  3. Kucera, G. T., Bortner, D. M. & Rosenberg, M. P. Dev. Biol. 173, 162–173 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Perry, W. L., Hustad, C. M., Swing, D. A., Jenkins, N. A. & Copeland, N. G. Genetics 140, 267–274 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Wilson, B. D. et al. Hum. Mol. Genet. 4, 223–230 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. Miller, M. W. et al. Genes Dev. 7, 454–467 (1993).

    Article  CAS  PubMed  Google Scholar 

  7. Lu, D. et al. Nature 371, 799–802 (1994).

    Article  ADS  CAS  PubMed  Google Scholar 

  8. Gantz, I. et al. J. Biol. Chem. 268, 15174–15179 (1993).

    CAS  PubMed  Google Scholar 

  9. Mountjoy, K. G., Mortrud, M. T., Low, M. J., Simerly, R. B. & Cone, R. D. Mol. Endocrinol. 8, 1298–1308 (1994).

    CAS  PubMed  Google Scholar 

  10. Hruby, V. J. et al. J. Med. Chem. 38, 3454–3461 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Gantz, I. et al. J. Biol. Chem. 268, 8246–8250 (1993).

    CAS  PubMed  Google Scholar 

  12. Roselli-Rehfuss, L. et al. Proc. Natl Acad. Sci. USA 90, 8856–8860 (1993).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wolff, G. L. Genetics 48, 1041–1058 (1963).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Al-Obeidi, F., Castrucci, A. M., Hadley, M. E. & Hruby, V. J. J. Med. Chem. 32, 2555–2561 (1989).

    Article  CAS  PubMed  Google Scholar 

  15. Watson, S. J., Akil, H., Richard, C. W. & Barchas, J. D. Nature 275, 226–228 (1978).

    Article  ADS  CAS  PubMed  Google Scholar 

  16. Jacobowitz, D. M. & O'Donohue, T. L. Proc. Natl Acad. Sci. USA 75, 6300–6304 (1978).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  17. Huszar, D. et al. Cell (in the press).

  18. Bergendahl, M., Wiemann, J. N., Clifton, D. K., Huhtaniemi, I. & Steiner, R. A. Neuroendocrinology 56, 913–920 (1992).

    Article  CAS  PubMed  Google Scholar 

  19. Brady, L. S., Smith, M. A., Gold, P. W. & Herkenham, M. Neuroendocrinology 52, 441–447 (1990).

    Article  CAS  PubMed  Google Scholar 

  20. Steiner, R. A., Kabigting, E., Lent, K. & Clifton, D. K. J. Neuroendocrinol. 6, 603–608 (1994).

    Article  CAS  PubMed  Google Scholar 

  21. Wilding, J. P. H. et al. Endocrinology 132, 1939–1944 (1993).

    Article  CAS  PubMed  Google Scholar 

  22. Erickson, J. C., Hollopeter, G. & Palmiter, R. D. Science 274, 1704–1707 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  23. Stephens, T. W. et al. Nature 377, 530–532 (1995).

    Article  ADS  CAS  PubMed  Google Scholar 

  24. Schwartz, M. W. et al. J. Clin. Invest. 98, 1101–1106 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kestersan, R. A., Huszar, D., Lynch, C. A., Sinerly, R. S. & Cone, R. D. Mol. Endocrinol. (submitted).

  26. Johnson, R. A. & Salomon, Y. Methods Enzymol. 195, 3–21 (1991).

    Article  CAS  PubMed  Google Scholar 

  27. Chen, W., Shields, T. S., Stork, P. J. S. & Cone, R. D. Anal. Biochem. 226, 349–354 (1995).

    Article  CAS  PubMed  Google Scholar 

  28. Laursen, S. E. & Belknap, J. K. J. Pharmacol. Methods 16, 355–357 (1986).

    Article  CAS  PubMed  Google Scholar 

Download references

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Fan, W., Boston, B., Kesterson, R. et al. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385, 165–168 (1997). https://doi.org/10.1038/385165a0

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