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


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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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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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).

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