A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors.
Melanocortin-4 receptor (Mc4r)-null mice exhibit late-onset obesity. To determine whether aberrant metabolism contributes to the obesity, food consumption by Mc4r-null mice was restricted to (pair-fed to) that consumed by wild-type (WT) mice. Pair-fed Mc4r-null females maintained body weights intermediate to that of WT and nonpair-fed Mc4r-null females, whereas pairfeeding normalized the body weights of Mc4r-null male mice. Fat pad and circulating leptin levels were elevated in both male and female pair-fed Mc4r-null mice compared with WT mice. Oxygen consumption of Mc4r-null mice with similar body weights as WT controls was reduced by 20%. Locomotor activity of young nonobese Mc4r-null males was significantly lower than that of WT males; however, locomotion of young nonobese females was normal. Core body temperature of Mc4r-null mice was normal, and they responded normally to cold exposure. Young nonobese Mc4r-null females were unable to induce uncoupling protein 1 (UCP1) in brown adipose tissue in response to peripheral leptin administration, whereas UCP1 mRNA was increased by 60% in the WT females. These results indicate that Mc4r deficiency enhances caloric efficiency, similar to that seen in the agouti obesity syndrome and in melanocortin-3 receptor-null mice.
Ste Marie
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Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Box 357370, Seattle, WA 98195, USA.
Miura
G I
GI
Marsh
D J
DJ
Yagaloff
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K
Palmiter
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RD
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007473:Ion Channels; D020738:Leptin / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins; D009043:Motor Activity; D009765:Obesity / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4; D018000:Receptors, Peptide / Q000235:genetics / Q000502:physiology*; D000071256:Uncoupling Protein 1
D002352:Carrier Proteins; D007473:Ion Channels; D020738:Leptin; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D044105:Receptor, Melanocortin, Type 4; D018000:Receptors, Peptide; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1