Divergence of melanocortin pathways in the control of food intake and energy expenditure

Nina Balthasar, Louise T. Dalgaard, Charlotte E. Lee, Jia Yu, Hisayuki Funahashi, Todd Williams, Manuel Ferreira, Vinsee Tang, Robert A. McGovern, Christopher D. Kenny, Lauryn M. Christiansen, Elizabeth Edelstein, Brian Choi, Olivier Boss, Carl Aschkenasi, Chen Yu Zhang, Kathleen Mountjoy, Toshiro Kishi, Joel K. Elmquist, Bradford B. Lowell

Research output: Contribution to journalArticle

651 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)493-505
Number of pages13
JournalCell
Volume123
Issue number3
DOIs
StatePublished - Nov 4 2005

Fingerprint

Receptor, Melanocortin, Type 4
Melanocortins
Energy Metabolism
Eating
Amygdala
Hypothalamus
Alleles
Energy balance
Transgenic Mice
Restoration
Neurons
Adipose Tissue
Obesity
Chemical activation
Fats

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Balthasar, N., Dalgaard, L. T., Lee, C. E., Yu, J., Funahashi, H., Williams, T., ... Lowell, B. B. (2005). Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell, 123(3), 493-505. https://doi.org/10.1016/j.cell.2005.08.035

Divergence of melanocortin pathways in the control of food intake and energy expenditure. / Balthasar, Nina; Dalgaard, Louise T.; Lee, Charlotte E.; Yu, Jia; Funahashi, Hisayuki; Williams, Todd; Ferreira, Manuel; Tang, Vinsee; McGovern, Robert A.; Kenny, Christopher D.; Christiansen, Lauryn M.; Edelstein, Elizabeth; Choi, Brian; Boss, Olivier; Aschkenasi, Carl; Zhang, Chen Yu; Mountjoy, Kathleen; Kishi, Toshiro; Elmquist, Joel K.; Lowell, Bradford B.

In: Cell, Vol. 123, No. 3, 04.11.2005, p. 493-505.

Research output: Contribution to journalArticle

Balthasar, N, Dalgaard, LT, Lee, CE, Yu, J, Funahashi, H, Williams, T, Ferreira, M, Tang, V, McGovern, RA, Kenny, CD, Christiansen, LM, Edelstein, E, Choi, B, Boss, O, Aschkenasi, C, Zhang, CY, Mountjoy, K, Kishi, T, Elmquist, JK & Lowell, BB 2005, 'Divergence of melanocortin pathways in the control of food intake and energy expenditure', Cell, vol. 123, no. 3, pp. 493-505. https://doi.org/10.1016/j.cell.2005.08.035
Balthasar N, Dalgaard LT, Lee CE, Yu J, Funahashi H, Williams T et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell. 2005 Nov 4;123(3):493-505. https://doi.org/10.1016/j.cell.2005.08.035
Balthasar, Nina ; Dalgaard, Louise T. ; Lee, Charlotte E. ; Yu, Jia ; Funahashi, Hisayuki ; Williams, Todd ; Ferreira, Manuel ; Tang, Vinsee ; McGovern, Robert A. ; Kenny, Christopher D. ; Christiansen, Lauryn M. ; Edelstein, Elizabeth ; Choi, Brian ; Boss, Olivier ; Aschkenasi, Carl ; Zhang, Chen Yu ; Mountjoy, Kathleen ; Kishi, Toshiro ; Elmquist, Joel K. ; Lowell, Bradford B. / Divergence of melanocortin pathways in the control of food intake and energy expenditure. In: Cell. 2005 ; Vol. 123, No. 3. pp. 493-505.
@article{03e73475b2e34f63ae624200d6698daf,
title = "Divergence of melanocortin pathways in the control of food intake and energy expenditure",
abstract = "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.",
author = "Nina Balthasar and Dalgaard, {Louise T.} and Lee, {Charlotte E.} and Jia Yu and Hisayuki Funahashi and Todd Williams and Manuel Ferreira and Vinsee Tang and McGovern, {Robert A.} and Kenny, {Christopher D.} and Christiansen, {Lauryn M.} and Elizabeth Edelstein and Brian Choi and Olivier Boss and Carl Aschkenasi and Zhang, {Chen Yu} and Kathleen Mountjoy and Toshiro Kishi and Elmquist, {Joel K.} and Lowell, {Bradford B.}",
year = "2005",
month = "11",
day = "4",
doi = "10.1016/j.cell.2005.08.035",
language = "English (US)",
volume = "123",
pages = "493--505",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",

}

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=27544450765&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=27544450765&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2005.08.035

DO - 10.1016/j.cell.2005.08.035

M3 - Article

C2 - 16269339

AN - SCOPUS:27544450765

VL - 123

SP - 493

EP - 505

JO - Cell

JF - Cell

SN - 0092-8674

IS - 3

ER -