title: The melanocortin-3 receptor is required for entrainment to meal intake.
abstract: Entrainment of anticipatory activity and wakefulness to nutrient availability is a poorly understood component of energy homeostasis. Restricted feeding (RF) paradigms with a periodicity of 24 h rapidly induce entrainment of rhythms anticipating food presentation that are independent of master clocks in the suprachiasmatic nucleus (SCN) but do require other hypothalamic structures. Here, we report that the melanocortin system, which resides in hypothalamic structures required for food entrainment, is required for expression of food entrainable rhythms. Food anticipatory activity was assessed in wild-type (WT) and melanocortin-3 receptor-deficient (Mc3r-/-) C57BL/J mice by wheel running, spontaneous locomotory movement, and measurement of wakefulness. WT mice housed in wheel cages subject to RF exhibited increased wheel activity during the 2 h preceding meal presentation, which corresponded with an increase in wakefulness around meal time and reduced wakefulness during the dark. WT mice also exhibited increased x- and z-movements centered around food initiation. The activity-based responses to RF were significantly impaired in mice lacking Mc3r. RF also failed to increase wakefulness in the 2 h before food presentation in Mc3r-/- mice. Food entrainment requires expression of Neuronal PAS domain 2 (Npas2) and Period2 (Per2) genes, components of the transcriptional machinery maintaining a clock rhythm. Analysis of cortical gene expression revealed severe abnormalities in rhythmic expression of clock genes (Bmal1, Npas2, Per2) under ad libitum and RF conditions. In summary, Mc3r are required for expression of anticipatory patterns of activity and wakefulness during periods of limited nutrient availability and for normal regulation of cortical clock function.
authors.affiliation: Neuropeptides Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 70808, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Sutton
authors.forename: Diego
authors.initials: D
authors.lastname: Perez-Tilve
authors.forename: Ruben
authors.initials: R
authors.lastname: Nogueiras
authors.forename: Jidong
authors.initials: J
authors.lastname: Fang
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.forename: Roger D
authors.initials: RD
authors.lastname: Cone
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Gimble
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Butler
mesh_terms: D056930:ARNTL Transcription Factors; D000818:Animals; D001066:Appetite / Q000235:genetics*; D001069:Appetite Regulation / Q000235:genetics*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics; D002540:Cerebral Cortex / Q000033:anatomy & histology / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics*; D005247:Feeding Behavior / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D007031:Hypothalamus / Q000033:anatomy & histology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D056950:Period Circadian Proteins; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D044104:Receptor, Melanocortin, Type 3 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D014851:Wakefulness / Q000235:genetics
chemical_list: D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D011333:Pro-Opiomelanocortin; D044104:Receptor, Melanocortin, Type 3; D014157:Transcription Factors; C538961:Bmal1 protein, mouse; C491259:Npas2 protein, mouse; C513312:Per2 protein, mouse