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The Journal of Neuroscience, May 15, 2001, 21(10):3639-3645
Hypothalamic, Metabolic, and Behavioral Responses to Pharmacological Inhibition of CNS Melanocortin Signaling in Rats
Tiziana Adage1, Anton J. W. Scheurink1, Sietse F. de Boer1, Koert de Vries1, Jan Pieter Konsman2, Folkert Kuipers3, Roger A. H. Adan4, Denis G. Baskin5, 7, Michael W. Schwartz6, and Gertjan van Dijk1 1 Department of Animal Physiology, University of Groningen, 9750 AA Haren, the Netherlands, 2 Department of Biomedicine and Surgery, Faculty of Health Sciences, University of Linköping, 58185 Linköping, Sweden, 3 Centre for Liver, Digestive, and Metabolic Diseases, Department of Pediatrics, University Hospital, 9713GZ Groningen, the Netherlands, 4 Department of Medical Pharmacology, Rudolph Magnus Institute, University of Utrecht, 3584CG Utrecht, the Netherlands, 5 Department of Medicine and Biological Structure, University of Washington, 6 Department of Medicine, University of Washington and Harborview Medical Center, Seattle, Washington 98104, and 7 Veterans Affairs Medical Center, Seattle, Washington 98108
The CNS melanocortin (MC) system is implicated as a mediator of the central effects of leptin, and reduced activity of the CNS MC system promotes obesity in both rodents and humans. Because activation of CNS MC receptors has direct effects on autonomic outflow and metabolism, we hypothesized that food intake-independent mechanisms contribute to development of obesity induced by pharmacological blockade of MC receptors in the brain and that changes in hypothalamic neuropeptidergic systems known to regulate weight gain [i.e., corticotropin-releasing hormone (CRH), cocaine-amphetamine-related transcript (CART), proopiomelanocortin (POMC), and neuropeptide Y (NPY)] would trigger this effect. Relative to vehicle-treated controls, third intracerebroventricular (i3vt) administration of the MC receptor antagonist SHU9119 to rats for 11 d doubled food and water intake (toward the end of treatment) and increased body weight (~14%) and fat content (~90%), hepatic glycogen content (~40%), and plasma levels of cholesterol (~48%), insulin (~259%), glucagon (~80%), and leptin (~490%), whereas spontaneous locomotor activity and body temperature were reduced. Pair-feeding of i3vt SHU9119-treated animals to i3vt vehicle-treated controls normalized plasma levels of insulin, glucagon, and hepatic glycogen content, but only partially reversed the elevations of plasma cholesterol (~31%) and leptin (~104%) and body fat content (~27%). Reductions in body temperature and locomotor activity induced by i3vt SHU9119 were not reversed by pair feeding, but rather were more pronounced. None of the effects found can be explained by peripheral action of the compound. The obesity effects occurred despite a lack in neuropeptide expression responses in the neuroanatomical range selected across the arcuate (i.e., CART, POMC, and NPY) and paraventricular (i.e., CRH) hypothalamus. The results indicate that reduced activity of the CNS MC pathway promotes fat deposition via both food intake-dependent and -independent mechanisms.
Key words: obesity; SHU9119; NPY; CRH; POMC; CART; cholesterol; leptin; hypothalamus; body temperature
Copyright © 2001 Society for Neuroscience 0270-6474/01/21103639-07$05.00/0
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