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Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass

Nature Genetics volume 26, pages 97–102 (2000)Cite this article

Abstract

Genetic1,2,3,4,5,6,7,8 and pharmacological6,9,10,11,12 studies have defined a role for the melanocortin-4 receptor (Mc4r) in the regulation of energy homeostasis. The physiological function of Mc3r, a melanocortin receptor expressed at high levels in the hypothalamus13, has remained unknown. We evaluated the potential role of Mc3r in energy homeostasis by studying Mc3r-deficient (Mc3r−/−) mice and compared the functions of Mc3r and Mc4r in mice deficient for both genes. The 4–6-month Mc3r−/− mice have increased fat mass, reduced lean mass and higher feed efficiency than wild-type littermates, despite being hypophagic and maintaining normal metabolic rates. (Feed efficiency is the ratio of weight gain to food intake.) Consistent with increased fat mass, Mc3r−/− mice are hyperleptinaemic and male Mc3r−/− mice develop mild hyperinsulinaemia. Mc3r−/− mice did not have significantly altered corticosterone or total thyroxine (T4) levels. Mice lacking both Mc3r and Mc4r become significantly heavier than Mc4r−/− mice. We conclude that Mc3r and Mc4r serve non-redundant roles in the regulation of energy homeostasis.

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Figure 1: Targeted disruption of the mouse Mc3r locus.
Figure 2: Growth curves (a,b) and body composition (c, d) of wild-type (+/+), Mc3r+/− (+/−) and Mc3r−/− (−/−) littermate mice.
Figure 3: Adipose tissue mass in wild-type (+/+), Mc3r+/− (+/−) and Mc3r−/− (−/−) littermates (a,b,c,d).
Figure 4: Plasma leptin (a), insulin (b), glucose (c), corticosterone (d) and total T4 (e) levels of wild-type (+/+), Mc3r+/− (+/−) and Mc3r−/− (−/−) littermates.
Figure 5: Food intake, weight gain and feed efficiency of individually housed male wild-type (+/+, n=11), Mc3r+/− (+/−, n=20) and Mc3r−/− (−/−, n=16) littermates were maintained on a regular chow diet.
Figure 6: Metabolic rate (a), locomotor activity (b,d) and fine movements (c,e) of individually housed Mc3r −/− (−/−) and wild-type (+/+) littermates.

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Acknowledgements

We thank D. Weinberg for providing rat Mc3r cDNA and J. Ronan for assistance in the histological evaluation of adipose tissues.

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Author notes

  1. Airu S. Chen and Donald J. Marsh: These authors contributed equally to this manuscript.

Authors and Affiliations

  1. Department of Obesity Research, Merck Research Laboratories, Rahway, New Jersey, USA

    Airu S. Chen, Donald J. Marsh, Myrna E. Trumbauer, Easter G. Frazier, Xiao-Ming Guan, Hong Yu, Charles I. Rosenblum, Aurawan Vongs, Yue Feng, Linhai Cao, Howard Y. Chen & Lex H.T. Van der Ploeg

  2. Department of Animal Pharmacology, Merck Research Laboratories, Rahway, New Jersey, USA

    Joseph M. Metzger, Alison M. Strack, Ramon E. Camacho, Theodore N. Mellin, Christian N. Nunes, William Min & D. Euan MacIntyre

  3. Department of Comparative Medicine, Merck Research Laboratories, Rahway, New Jersey, USA

    Jill Fisher & Shobhna Gopal-Truter

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Correspondence to Lex H.T. Van der Ploeg.

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Chen, A., Marsh, D., Trumbauer, M. et al. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet 26, 97–102 (2000). https://doi.org/10.1038/79254

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