The mahogany protein is a receptor involved in suppression of obesity (original) (raw)

• Letter
• Published: 11 March 1999
• Sonja H. McGrail1,
• James Vitale1,
• Elizabeth A. Woolf1,
• Barry J. Dussault Jr1,
• Lisa DiRocco1,
• Lisa Holmgren1,
• Jill Montagno1,
• Peer Bork2,3,
• Dennis Huszar1,
• Victoria Fairchild-Huntress1,
• Pei Ge1,
• John Keilty1,
• Chris Ebeling4,
• Linda Baldini4,
• Julie Gilchrist4,
• Paul Burn5,
• George A. Carlson4 &
• …
• Karen J. Moore1

Nature volume 398, pages 148–152 (1999)Cite this article

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Abstract

Genetic studies have shown that mutations within the mahogany locus1 suppress the pleiotropic phenotypes, including obesity, of the agouti-lethal-yellow mutant2,3. Here we identify the mahogany gene and its product; this study, to our knowledge, represents the first positional cloning of a suppressor gene in the mouse. Expression of the mahogany gene is broad; however, in situ hybridization analysis emphasizes the importance of its expression in the ventromedial hypothalamic nucleus, a region that is intimately involved in the regulation of body weight and feeding. We present new genetic studies that indicate that the mahogany locus does not suppress the obese phenotype of the melanocortin-4-receptor null allele4 or those of the monogenic obese models (Lep db, tub and Cpe fat). However, mahogany can suppress diet-induced obesity, the mechanism of which is likely to have implications for therapeutic intervention in common human obesity. The amino-acid sequence of the mahogany protein suggests that it is a large, single-transmembrane-domain receptor-like molecule, with a short cytoplasmic tail containing a site that is conserved between Caenorhabditis elegans and mammals. We propose two potential, alternative modes of action for mahogany: one draws parallels with the mechanism of action of low-affinity proteoglycan receptors such as fibroblast growth factor and transforming growth factor-β, and the other suggests that mahogany itself is a signalling receptor.

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Acknowledgements

We thank I. Jackson for the gift of the C3H/He-mgL /mgL mice; J. Smutko for mapping the human mg orthologue; and M. Donovan, B. Tepper and L. Tartaglia for helpful advice. This work was supported by Hoffman-La Roche Inc.

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Authors and Affiliations

1. Millennium Pharmaceuticals, Inc., 640 Memorial Drive, Cambridge, 02139, Massachusetts, USA
   Deborah L. Nagle, Sonja H. McGrail, James Vitale, Elizabeth A. Woolf, Barry J. Dussault Jr, Lisa DiRocco, Lisa Holmgren, Jill Montagno, Dennis Huszar, Victoria Fairchild-Huntress, Pei Ge, John Keilty & Karen J. Moore
2. European Molecular Biology Laboratories, Meyerhfstrasse 1, 69012, Heidelberg, Germany
   Peer Bork
3. Max-Delbrck-Centrum fr Molekulare Medizin, Robert-Rssle-Strasse 10, 13092, Berlin, Germany
   Peer Bork
4. McLaughlin Research Institute for Biomedical Sciences, 1520 23rd Street South, Great Falls, 59405, Montana, USA
   Chris Ebeling, Linda Baldini, Julie Gilchrist & George A. Carlson
5. Department of Metabolic Diseases, Hoffman-La Roche, Inc., Nutley, 07110, New Jersey, USA
   Paul Burn

Authors

1. Deborah L. Nagle
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2. Sonja H. McGrail
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3. James Vitale
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4. Elizabeth A. Woolf
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5. Barry J. Dussault Jr
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6. Lisa DiRocco
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7. Lisa Holmgren
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8. Jill Montagno
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9. Peer Bork
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10. Dennis Huszar
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11. Victoria Fairchild-Huntress
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12. Pei Ge
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13. John Keilty
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14. Chris Ebeling
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15. Linda Baldini
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16. Julie Gilchrist
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17. Paul Burn
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18. George A. Carlson
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19. Karen J. Moore
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Corresponding author

Correspondence toKaren J. Moore.

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Nagle, D., McGrail, S., Vitale, J. et al. The mahogany protein is a receptor involved in suppression of obesity.Nature 398, 148–152 (1999). https://doi.org/10.1038/18210

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• Received: 07 October 1998
• Accepted: 08 January 1999
• Issue Date: 11 March 1999
• DOI: https://doi.org/10.1038/18210

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