Targeted deletion of melanocortin receptor subtypes 3 and 4, but not CART, alters nutrient partitioning and compromises behavioral and metabolic responses to leptin.
Mouse lines with targeted disruption of the cocaine amphetamine-related transcript (CART), melanocortin receptor 3 (MCR3), or melanocortin receptor 4 (MCR4) were used to assess the role of each component in mediating the anorectic and metabolic effects of leptin, and in regulating the partitioning of nutrient energy between fat and protein deposition. Leptin was administered over a 3 day period using either intraperitoneal or intracerebroventricular routes of injection. The absence of MCR4 blocked leptin's ability to increase UCP1 mRNA in both brown and white adipose tissue, but not its ability to reduce food consumption. In contrast, deletion of MCR3 compromised leptin's ability to reduce food consumption, but not its ability to reduce fat deposition or increase UCP1 expression in adipose tissue. Leptin-dependent effects on food consumption and adipocyte gene expression were unaffected by the absence of CART. Repeated measures of body composition over time indicate that the absence of either MCR3 or MCR4, but not CART, increased lipid deposition and produced comparable degrees of adiposity in both lines. Moreover, modest increases in fat content of the diet (4 to 11%) accentuated fat deposition and produced a rapid and comparable 10-12% increase in % body fat in both genotypes. The results indicate that nutrient partitioning, as well as the anorectic and metabolic responses to leptin, are dependent on integrated but separable inputs from the melanocortin 3 and 4 receptor subtypes.
Zhang
Yubin
Y
Division of Experimental Obesity, Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA.
Kilroy
Gail E
GE
Henagan
Tara M
TM
Prpic-Uhing
Vera
V
Richards
William G
WG
Bannon
Anthony W
AW
Mynatt
Randall L
RL
Gettys
Thomas W
TW
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001823:Body Composition / Q000187:drug effects*; D002352:Carrier Proteins / Q000235:genetics; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D007473:Ion Channels; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D044104:Receptor, Melanocortin, Type 3 / Q000235:genetics / Q000502:physiology*; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000502:physiology*; D054411:Receptors, Leptin; D000071256:Uncoupling Protein 1; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
D002352:Carrier Proteins; D007473:Ion Channels; D020738:Leptin; C470053:Mc3r protein, mouse; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D054411:Receptors, Leptin; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; C515447:leptin receptor, mouse