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Published on: September 7, 2013
Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass
A S Chen1, D J Marsh, M E Trumbauer
1Department of Obesity Research, Merck Research Laboratories, Rahway, New Jersey, USA.
Abstract:
Genetic and pharmacological 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, 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.
Insights
The melanocortin-3 receptor (Mc3r) plays a key role in regulating body weight and metabolism. Mc3r-deficient mice show altered body composition and increased feed efficiency, indicating distinct functions from Mc4r.
Area of Science:
- Neuroendocrinology
- Metabolic Regulation
- Obesity Research
Background:
- Melanocortin-4 receptor (Mc4r) is known to regulate energy homeostasis.
- The physiological role of melanocortin-3 receptor (Mc3r) in energy balance remains unclear.
- Mc3r is highly expressed in the hypothalamus, a key brain region for metabolic control.
Purpose of the Study:
- To investigate the role of Mc3r in energy homeostasis.
- To compare the functions of Mc3r and Mc4r in metabolic regulation.
- To characterize the phenotype of Mc3r-deficient mice.
Main Methods:
- Generation and analysis of Mc3r-deficient (Mc3r(-/-)) mice.
- Phenotypic characterization including body composition, feed efficiency, and metabolic rates.
- Comparative studies of Mc3r(-/-), Mc4r(-/-), and double-deficient (Mc3r(-/-)/Mc4r(-/-)) mice.
Main Results:
- Mc3r(-/-) mice exhibited increased fat mass, reduced lean mass, and higher feed efficiency despite reduced food intake.
- Mc3r(-/-) mice showed hyperleptinemia and mild hyperinsulinemia in males.
- Mice lacking both Mc3r and Mc4r were significantly heavier than Mc4r(-/-) mice, suggesting non-redundant roles.
Conclusions:
- Mc3r plays a significant role in regulating energy homeostasis, distinct from Mc4r.
- Mc3r influences body composition, feed efficiency, and hormonal profiles related to metabolism.
- Mc3r and Mc4r have non-redundant functions in the overall regulation of energy balance.
