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.
MeSH terms
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Adipose Tissue / metabolism*
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Age Factors
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Animals
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Blotting, Southern
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Body Temperature
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Body Weight*
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Calorimetry
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Corticosterone / biosynthesis
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Feeding Behavior
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Female
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Genotype
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Glucose / biosynthesis
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Humans
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Hyperinsulinism / genetics
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In Situ Hybridization
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Insulin / biosynthesis
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Leptin / biosynthesis
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Male
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Mice
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Mice, Knockout
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Models, Genetic
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Motor Activity
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Obesity / genetics
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Oligopeptides / pharmacology
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Phenotype
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Protein Isoforms
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Receptor, Melanocortin, Type 3
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Receptor, Melanocortin, Type 4
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Receptors, Corticotropin / chemistry
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Receptors, Corticotropin / genetics*
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Receptors, Corticotropin / physiology*
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Receptors, Peptide / genetics
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Receptors, Peptide / metabolism
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Recombination, Genetic
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Thyroxine / biosynthesis
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Time Factors
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Tissue Distribution
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alpha-MSH / analogs & derivatives
Substances
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Insulin
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Leptin
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Oligopeptides
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Protein Isoforms
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Receptor, Melanocortin, Type 3
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Receptor, Melanocortin, Type 4
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Receptors, Corticotropin
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Receptors, Peptide
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acetyl-norleucyl(4)-(aspartyl(5)-histidyl(6)-phenylalanyl(7)-arginyl(8)-tryptophyl(9)-lysyl(10))cyclo-alpha-MSH(4-10)amide
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alpha-MSH
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Glucose
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Thyroxine
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Corticosterone