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The mahogany protein is a receptor involved in suppression of obesity

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

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 (Lepdb, tub and Cpefat). 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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Figure 1: Effect of mg on Mc4r−/− -induced weight gain in females.
Figure 2: Effect of mg on the monogenic obese mutants tub, Cpefat and Leprdb and on obesity induced by a high-fat diet.
Figure 3: Genetic and physical map of the region surrounding the mg locus.
Figure 4: Expression patterns of mg.
Figure 5: Domains of the mahogany protein.

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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

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Correspondence to Karen 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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