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 journalArticlepeer-review

831 Scopus citations

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
Externally publishedYes

Bibliographical note

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.

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