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Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin

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Abstract

Pro-opiomelanocortin (POMC)-derived peptides (the melanocortins adrenocorticotropin, α-, β- and γ-melanocyte stimulating hormone; and the endogenous opioid β-endorphin) have a diverse array of biological activities, including roles in pigmentation, adrenocortical function and regulation of energy stores, and in the immune system and the central and peripheral nervous systems1. We show here that mice lacking the POMC-derived peptides have obesity, defective adrenal development and altered pigmentation. This phenotype is similar to that of the recently identified human POMC-deficient patients2. When treated with a stable α-melanocyte-stimulating hormone agonist, mutant mice lost more than 40% of their excess weight after 2 weeks. Our results identify the POMC-null mutant mouse as a model for studying the human POMC-null syndrome, and indicate the therapeutic use of peripheral melanocortin in the treatment of obesity.

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Figure 1: Generation of POMC-null mice.
Figure 2: Obesity and altered pigmentation in POMC-null mice.
Figure 3: Adrenal insufficiency in POMC-null mice.
Figure 4: Effect of MSH treatment.

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Acknowledgements

We thank J. Elliott and S. Bui for their technical assistance, M. Glynn for art work, B. Martin for oligonucleotide synthesis, E.I. Ginns for support of the early phases of the work and M. Davisson for comments on an earlier version of the manuscript. This work was supported by a generous grant from the Board of Trustees of the Eleanor Roosevelt Institute, Denver, Colorado (M.B.B.) and by the Samuel Roberts Noble Foundation, Ardmore, Oklahoma (U.H.).

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Author notes

  1. Linda Yaswen

    Present address: Metamorphix, 1450 South Rolling Road, Baltimore, Maryland, 21227, USA

  2. Nicole Diehl

    Present address: University of Vermont, Given C-321, Burlington, Vermont, 05405, USA

Authors and Affiliations

  1. Unit on Molecular Genetics, Clinical Neuroscience Branch, NIMH, 49 Convent Drive, Bethesda, 20892, Maryland, USA

    Linda Yaswen & Nicole Diehl

  2. Eleanor Roosevelt Institute, 1899 Gaylord Street, Denver, 80206, Colorado, USA

    Miles B. Brennan

  3. Developmental Biology Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, 73104, Oklahoma, USA

    Ute Hochgeschwender

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  1. Linda Yaswen
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  4. Ute Hochgeschwender
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Correspondence to Ute Hochgeschwender.

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Yaswen, L., Diehl, N., Brennan, M. et al. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat Med 5, 1066–1070 (1999). https://doi.org/10.1038/12506

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