TY - JOUR
T1 - Divergence of melanocortin pathways in the control of food intake and energy expenditure
AU - Balthasar, Nina
AU - Dalgaard, Louise T.
AU - Lee, Charlotte E.
AU - Yu, Jia
AU - Funahashi, Hisayuki
AU - Williams, Todd
AU - Ferreira, Manuel
AU - Tang, Vinsee
AU - McGovern, Robert A.
AU - Kenny, Christopher D.
AU - Christiansen, Lauryn M.
AU - Edelstein, Elizabeth
AU - Choi, Brian
AU - Boss, Olivier
AU - Aschkenasi, Carl
AU - Zhang, Chen Yu
AU - Mountjoy, Kathleen
AU - Kishi, Toshiro
AU - Elmquist, Joel K.
AU - Lowell, Bradford B.
N1 - Funding Information:
This work was supported by grants from the NIH to B.B.L. and J.K.E. and by Takeda Pharmaceutical Company, Ltd., Japan. N.B. was supported by The Wellcome Trust, United Kingdom, an EASD-ADA and a BONRC grant. L.T.D. was supported by a grant from the Danish Medical Research Council. The authors would like to thank Clifford B. Saper for stimulating discussions.
PY - 2005/11/4
Y1 - 2005/11/4
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2005.08.035
DO - 10.1016/j.cell.2005.08.035
M3 - Article
C2 - 16269339
AN - SCOPUS:27544450765
SN - 0092-8674
VL - 123
SP - 493
EP - 505
JO - Cell
JF - Cell
IS - 3
ER -