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Hypothalamic, Metabolic, and Behavioral Responses to Pharmacological Inhibition of CNS Melanocortin Signaling in Rats
Open accessAbstract
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.
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“Central administration of both NPY and the melanocortin-3/4 receptor antagonist, SHU9119, cause insulin resistance and glucose intolerance via mechanisms independent of their effects on food intake (1, 109, 188).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [1]
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Metadata
- Authors
- Adage, T., Scheurink, A. J. W., de Boer, S. F., de Vries, K., Konsman, J. P., Kuipers, F., Adan, R. A. H., Baskin, D. G., Schwartz, M. W., & van Dijk, G.
- Affiliations
- University of Groningen (NL)
- Linköping University (SE)
- University Medical Center Groningen (NL)
- Utrecht University (NL)
- University of Washington (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2001-05-15
- Volume
- 21
- Issue
- 10
- Pages
- 3639-3645
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6762466
- OpenAlex
- W1912270743
- Cited by
- 106
- References
- 46
- Citations by year
- 2023: 1 · 2022: 1 · 2020: 2 · 2018: 3 · 2017: 1 · 2015: 3 · 2014: 5 · 2013: 3 · 2012: 3
- FWCI
- 2.61
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
- HAL (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (903-39-157)
- National Institutes of Health (2r01dk012829-36)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 12829, DK17844, DK-6339, DK 53109, R01DK053109)
- National Institute of Neurological Disorders and Stroke (NS-32273, R01NS032273)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- melanocortin system, SHU9119, obesity, dietary intake, hypothalamus, corticotropin-releasing factor, proopiomelanocortin, neuropeptide Y, leptin, liver glycogen, serum cholesterol, insulin, glucagon, body temperature, locomotor activity, pair feeding, fat deposition
- MeSH terms
- Animals, Behavior, Animal, Body Composition, Body Temperature, Cholesterol, Drinking, Eating, Glucagon, Hypothalamus, Injections, Intraventricular, Insulin, Male, Motor Activity, Melanocyte-Stimulating Hormones, Obesity, Pro-Opiomelanocortin, RNA, Messenger, Signal Transduction, Rats, Wistar, Receptors, Corticotropin, Neurotransmitter Agents, Leptin, Receptors, Melanocortin, Rats
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