The protein product of the gene called leptin (leptos means thin) is considered to be the major player in the regulation of the body fat. This, 16 kd, protein acts as a lipostat and by signalling to the hypothalamus regulates the energy expenditure and food intake (Diagram). ob/ob mutant mice that lack leptin are obese. In addition, mutations in the leptin receptor which is found in the db mice, and corpulent and Zuker rats is also associated with obesity. Leptin deficiency results in the elevation of the hypothalamic neuropeptide Y (NPY) in the hypothalamus. This peptide seems to be a partner of leptin in the regulation of body fat by participation in the engergy balance and neuroendocrine signalling.Chronic administration of the NPY into the hypothalamus of normal animals mimics the phenotype associated with leptin deficiency including hyperphagia, obesity, reduced thermogenesis, decreased fertility and inhibition of growth hormone production. The gene inactivation of the NPY, however, was not associated with changes in the body weight, the foot intake or the body fat. This unexpected finding is now explained by the data reported by Erickson et al in the December 6, 1996 issue of Science. These authors report that generation of deficiency in the NPY gene in the ob/ob mice leads to less obesity than that observed in the ob/ob mutant mice. In addition, these animals exhibit a less severe diabetes, sterility and somatotrophic defects. This suggests that the weight gain in the ob/ob leptin deficient mice may, to some extent, be mediated by the increased production of NPY. The partial and not total recovery from the effects of leptin deficiency in the ob/ob mice deficient in NPY suggests that the action of leptin is not confined to the regulation of the NPY and that other proteins may be implicated in the regulation of the body fat. Additional members of this regulatory pathway seems to be the agouti protein, a 131 amino acid protein, and its respective receptor, melanocortin receptor-4 (MRC-4) which exists in the arcuate nucleus of the hypothalamus. The outcome of the binding of the agouti to MRC-4 is suppression of the feeding. The report by Huszar et al in the Cell that the MRC-4 knockout mice gain weight is consistent with the hypothesis that agouti-melanocortin receptor-4 binding is involved in the regulation of the body fat. Taken together, the available findings support the viewpoint that the regulation of the body fat by the hypothalamus involves multiple proteins and their respective receptors.

REFERENCES:

NEUROPEPTIDE Y (NPY)

1. Allen, J. M.; Bloom, S. R. :

Neuropeptide Y: a putative neurotransmitter. Neurochem. Int. 8: 1-8, 1986.

2. Bahary, N.; Zorich, G.; Pachter, J. E.; Leibel, R. L.; Friedman, J. M. :

Molecular genetic linkage maps of mouse chromosomes 4 and 6. Genomics 11: 33-47, 1991.
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3. Baker, E.; Hort, Y. J.; Ball, H.; Sutherland, G. R.; Shine, J.; Herzog, H. :

Assignment of the human neuropeptide Y gene to chromosome 7p15.1 by nonisotopic in situ hybridization. Genomics 26: 163-164, 1995.
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4. Dockray, G. J. :

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Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science 274: 1704-1706, 1996.

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Neuropeptide Y: a putative neurotransmitter. Neurochem. Int. 8: 13-22, 1986.

7. Meisler, M. H.; Spence, J. E.; Dixon, J. E.; Caldwell, R. M.; Minth, C. D.; Beaudet, A. L. :

Exclusion of close linkage between the loci for cystic fibrosis and neuropeptide Y on human chromosome 7. Cytogenet. Cell Genet. 44: 175-176, 1987.
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8. Minth, C. D.; Andrews, P. C.; Dixon, J. E. :

Characterization, sequence, and expression of the cloned human neuropeptide Y gene. J. Biol. Chem. 261: 11974-11979, 1986.
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9. Minth, C. D.; Bloom, S. R.; Polak, J. M.; Dixon, J. E. :

Cloning, characterization, and DNA sequence of a human cDNA encoding neuropeptide tyrosine. Proc. Nat. Acad. Sci. 81: 4577-4581, 1984.
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Assignment of the related pancreatic polypeptide (PPY) and neuropeptide Y (NPY) genes to regions on human chromosomes 17 and 7. (Abstract) Cytogenet. Cell Genet. 40: 759 only, 1985.

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Genes encoding pancreatic polypeptide and neuropeptide Y are on human chromosomes 17 and 7. J. Clin. Invest. 77: 1038-1041, 1986.
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12. Terenghi, G.; Polak, J. M.; Hamid, Q.; O'Brien, E.; Denny, P.; Legon, S.; Dixon, J.; Minth, C. D.; Palay, S. L.; Yasargil, G.; Chan-Palay, V. :

Localization of neuropeptide Y mRNA in neurons of human cerebral cortex by means of in situ hybridization with a complementary RNA probe. Proc. Nat. Acad. Sci. 84: 7315-7318, 1987.
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1. Klebig, M. L.; Wilkinson, J. E.; Geisler, J. G.; Woychik, R. P. :

Ectopic expression of the agouti gene in transgenic mice causes obesity, features of type II diabetes, and yellow fur. Proc. Nat. Acad. Sci. 92: 4728-4732, 1995.
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Molecular structure and chromosomal mapping of the human homolog of the agouti gene. Proc. Nat. Acad. Sci. 91: 9760-9764, 1994.
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Mechanisms for the pleiotropic effects of the agouti gene. Proc. Nat. Acad. Sci. 92: 4721-4724, 1995.
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Structure and function of ASP, the human homolog of the mouse agouti gene. Hum. Molec. Genet. 4: 223-230, 1995.

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Agouti regulation of intracellular calcium: role in the insulin resistance of viable yellow mice. Proc. Nat. Acad. Sci. 92: 4733-4737, 1995.
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1. Gantz, I.; Miwa, H.; Konda, Y.; Shimoto, Y.; Tashiro, T.; Watson, S. J.; DelValle, J.; Yamada, T. :

Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. J. Biol. Chem. 268: 15174-15179, 1993.
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2. Huszar, D.; Lynch, C. A.; Fairchild-Huntress, V.; Dunmore, J. H.; Fang, Q.; Berkemeier, L. R.; Gu, W.; Kesterson, R. A.; Boston, B. A.; Cone, R. D.; Smith, F. J.; Campfield, L. A.; Burn, P.; Lee, F. :

Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88: 131-141, 1997.

3. Magenis, R. E.; Smith, L.; Nadeau, J. H.; Johnson, K. R.; Mountjoy, K. G.; Cone, R. D. :

Mapping of the ACTH, MSH, and neural (MC3 and MC4) melanocortin receptors in the mouse and human. Mammalian Genome 5: 503-508, 1994.
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