Divergence of melanocortin pathways in the control of food intake and energy expenditure.
Activation of melanocortin-4-receptors (MC4Rs) reduces body fat stores by decreasing food intake and increasing energy expenditure. MC4Rs are expressed in multiple CNS sites, any number of which could mediate these effects. To identify the functionally relevant sites of MC4R expression, we generated a loxP-modified, null Mc4r allele (loxTB Mc4r) that can be reactivated by Cre-recombinase. Mice homozygous for the loxTB Mc4r allele do not express MC4Rs and are markedly obese. Restoration of MC4R expression in the paraventricular hypothalamus (PVH) and a subpopulation of amygdala neurons, using Sim1-Cre transgenic mice, prevented 60% of the obesity. Of note, increased food intake, typical of Mc4r null mice, was completely rescued while reduced energy expenditure was unaffected. These findings demonstrate that MC4Rs in the PVH and/or the amygdala control food intake but that MC4Rs elsewhere control energy expenditure. Disassociation of food intake and energy expenditure reveals unexpected divergence in melanocortin pathways controlling energy balance.
Balthasar
Nina
N
Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Avenue, Boston, Massachusetts 02215, USA.
Dalgaard
Louise T
LT
Lee
Charlotte E
CE
Yu
Jia
J
Funahashi
Hisayuki
H
Williams
Todd
T
Ferreira
Manuel
M
Tang
Vinsee
V
McGovern
Robert A
RA
Kenny
Christopher D
CD
Christiansen
Lauryn M
LM
Edelstein
Elizabeth
E
Choi
Brian
B
Boss
Olivier
O
Aschkenasi
Carl
C
Zhang
Chen-yu
CY
Mountjoy
Kathleen
K
Kishi
Toshiro
T
Elmquist
Joel K
JK
Lowell
Bradford B
BB
D000679:Amygdala / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D004435:Eating / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology*; D019426:Integrases / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000096:biosynthesis* / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D019426:Integrases; D044105:Receptor, Melanocortin, Type 4; D012097:Repressor Proteins; C101750:Sim1 protein, mouse; C045073:Cre recombinase