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The Journal of Neuroscience, November 26, 2008, 28(48):12946-12955; doi:10.1523/JNEUROSCI.3615-08.2008
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Behavioral/Systems/Cognitive
The Melanocortin-3 Receptor Is Required for Entrainment to Meal Intake
Gregory M. Sutton,1 Diego Perez-Tilve,3 Ruben Nogueiras,3,4 Jidong Fang,5 Jason K. Kim,6 Roger D. Cone,7 Jeffrey M. Gimble,2 Matthias H. Tschöp,3,4 andAndrew A. Butler1,2 1Neuropeptides Laboratory, 2Clinical Nutrition Research Unit, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 70808, 3Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany, 4Department of Psychiatry, Obesity Research Centre, University of Cincinnati, Cincinnati, Ohio 45226, Departments of 5Psychiatry and 6Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, and 7Center for the Study of Weight Regulation and Associated Disorders and the Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239-3098
Correspondence should be addressed to Andrew A. Butler, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808. Email: butleraa{at}pbrc.edu
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.
Key words: circadian rhythms; POMC; proopiomelanocortin; entrainment; waking; sleep; food; neuropeptide; arousal; rhythm
Received July 30, 2008; revised Sept. 19, 2008; accepted Oct. 14, 2008.
Correspondence should be addressed to Andrew A. Butler, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808. Email: butleraa{at}pbrc.edu
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