Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass.
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.
Chen
A S
AS
Department of Obesity Research, Merck Research Laboratories, Rahway, New Jersey, USA.
Marsh
D J
DJ
Trumbauer
M E
ME
Frazier
E G
EG
Guan
X M
XM
Yu
H
H
Rosenblum
C I
CI
Vongs
A
A
Feng
Y
Y
Cao
L
L
Metzger
J M
JM
Strack
A M
AM
Camacho
R E
RE
Mellin
T N
TN
Nunes
C N
CN
Min
W
W
Fisher
J
J
Gopal-Truter
S
S
MacIntyre
D E
DE
Chen
H Y
HY
Van der Ploeg
L H
LH
D000273:Adipose Tissue / Q000378:metabolism*; D000367:Age Factors; D000818:Animals; D015139:Blotting, Southern; D001831:Body Temperature; D001835:Body Weight; D002151:Calorimetry; D003345:Corticosterone / Q000096:biosynthesis; D005247:Feeding Behavior; D005260:Female; D005838:Genotype; D005947:Glucose / Q000096:biosynthesis; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics; D017403:In Situ Hybridization; D007328:Insulin / Q000096:biosynthesis; D020738:Leptin / Q000096:biosynthesis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D009043:Motor Activity; D009765:Obesity / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology; D010641:Phenotype; D020033:Protein Isoforms; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic; D013974:Thyroxine / Q000096:biosynthesis; D013997:Time Factors; D014018:Tissue Distribution; D000521:alpha-MSH / Q000031:analogs & derivatives
D007328:Insulin; D020738:Leptin; D009842:Oligopeptides; D020033:Protein Isoforms; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D018000:Receptors, Peptide; C105974:acetyl-norleucyl(4)-(aspartyl(5)-histidyl(6)-phenylalanyl(7)-arginyl(8)-tryptophyl(9)-lysyl(10))cyclo-alpha-MSH(4-10)amide; D000521:alpha-MSH; D005947:Glucose; D013974:Thyroxine; D003345:Corticosterone