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

AS Chen, DJ Marsh, ME Trumbauer, EG Frazier… - Nature …, 2000 - nature.com
AS Chen, DJ Marsh, ME Trumbauer, EG Frazier, XM Guan, H Yu, CI Rosenblum, A Vongs…
Nature genetics, 2000nature.com
Abstract Genetic 1, 2, 3, 4, 5, 6, 7, 8 and pharmacological 6, 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 hypothalamus 13, 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 …
Abstract
Genetic 1, 2, 3, 4, 5, 6, 7, 8 and pharmacological 6, 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 hypothalamus 13, 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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