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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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“SHU9119 prevented the antipyretic but not the IL-6 suppressing effect of alpha-MSH.”
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“One pathway through which leptin may influence PA is via activation of the melanocortin-4 receptor in the arcuate nucleus [38,39].”
BackgroundFranks, P. W., Loos, R. J. F., Brage, S., O’Rahilly, S., Wareham, N. J., & Ekelund, U. (2007) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01022.2006 · Cited by 18
“A possible pathway through which leptin influences the behavior of physical activity is via activation of the melanocortin-4 receptor in the arcuate nucleus, a notion that is supported by animal and human studies (1, 23, 25, 29).”
do Carmo, J. M., Bassi, M., da Silva, A. A., & Hall, J. E. (2011) · Hypertension · doi:10.1161/hypertensionaha.110.163931 · Cited by 17
Age-related alterations in the central thermoregulatory responsiveness to alpha-MSH
Rostás, I., Füredi, N., Tenk, J., Mikó, A., Solymár, M., Soós, S., Székely, M., Pétervári, E., & Balaskó, M. (2015) · Journal of Thermal Biology · doi:10.1016/j.jtherbio.2015.01.004 · Cited by 16
Reinoß, P., Ciglieri, E., Minère, M., Bremser, S., Klein, A., Löhr, H., Fuller, P. M., Büschges, A., Kloppenburg, P., Fenselau, H., et al. (2020) · Current Biology · doi:10.1016/j.cub.2020.08.103 · Cited by 16
“Consistent with this, administration of the Mc4r antagonist SHU9119 results in decreased activity in mice [8] and Mc4r-deficient mice are hypoactive even before they become obese [9].”
BackgroundKim, J. G., Park, B. S., Yun, C. H., Kim, H. J., Kang, S. S., D'Elia, A. V., Damante, G., Lee, K., Park, J. W., Kim, E. S., et al. (2011) · Diabetes · doi:10.2337/db10-0183 · Cited by 16
van Dijk, G., de Vries, K., Nyakas, C. J., Buwalda, B., Adage, T., Kuipers, F., Kas, M. J., Adan, R. A. H., Wilkinson, C. W., Thiele, T. E., et al. (2005) · Endocrinology · doi:10.1210/en.2005-0472 · Cited by 16
“Determination of liver glycogen content was assessed as previously described (13).”
MethodSelf-citationFuel homeostasis and locomotor behavior: role of leptin and melanocortin pathways
Ceccarini, G., Maffei, M., Vitti, P., & Santini, F. (2014) · Journal of Endocrinological Investigation · doi:10.1007/s40618-014-0225-z · Cited by 16
de Vaca, S. C., Hao, J., Afroz, T., Krahne, L., & Carr, K. D. (2005) · Peptides · doi:10.1016/j.peptides.2005.03.041 · Cited by 15
MTII administered peripherally reduces fat without invoking apoptosis in rats
Choi, Y., Li, C., Hartzell, D. L., Lin, J., Della‐Fera, M. A., & Baile, C. A. (2003) · Physiology & Behavior · doi:10.1016/s0031-9384(03)00118-5 · Cited by 14
A gene–diet interaction controlling relative intake of dietary carbohydrates and fats
Nelson, N. G., Wu, L., Maier, M. T., Lam, D., Cheang, R. T., Alba, D., Huang, A., Neumann, D. A., Hill, T., Vagena, E., et al. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101442 · Cited by 13
“Little is known about the functional relationship between cholesterol and hypothalamic neuronal functions, however, acute antagonism of the central melanocortin receptors in rodents increases circulating cholesterol levels independent of food intake and body weight [20,21].”
BackgroundIs insulin resistance a disorder of the brain?
Undurti, N. D. (2010) · Frontiers in bioscience · doi:10.2741/3671 · Cited by 13
Change in CCK-8 response after diet-induced obesity and MC3/4-receptor blockade
Chandler-Laney, P. C., Wauford, P. K., Oswald, K. D., Maldonado, C. R., & Hagan, M. (2004) · Peptides · doi:10.1016/j.peptides.2003.12.015 · Cited by 13
The neural control of feeding in elasmobranchs: A review and working model
Demski, L. S. (2011) · Environmental Biology of Fishes · doi:10.1007/s10641-011-9827-x · Cited by 12
“α-MSH is an appetite-suppressing peptide hormone present in the arcuate nucleus in mammals (Adage et al. 2001; Arora and Anubhuti 2006; Blouet and Schwartz 2010) and the LTN in teleosts (Volkoff et al.”
BackgroundInfluentialLew, P. S., Wong, D., Yamaguchi, T. N., Leckström, A., Schwartz, J., Dodd, J. G., & Mizuno, T. M. (2009) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y09-074 · Cited by 14
Gautron, L., Cravo, R. M., Elmquist, J. K., & Elias, C. F. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.02.024 · Cited by 12
“MC4-R expressing neurons regulate a variety of functions including food intake and energy expenditure (Cowley et al., 1999, Adage et al., 2001, Butler et al., 2001, Farooqi et al., 2003, Krakoff et al., 2008), lipid mobilization (Nogueiras et al., 2007), cardiovascular responses (Tallam et al.,…”
BackgroundEster, W. A., Houghton, L. C., Lumey, L. H., Michels, K. B., Hoek, H. W., Wei, Y., Susser, E., Cohn, B. A., & Terry, M. B. (2017) · American Journal of Epidemiology · doi:10.1093/aje/kww222 · Cited by 11
“Heinsbroek and van Dijk (43) showed in rats that brain melanocortin receptor blockade during pregnancy induced GWG and increased the body weight of offspring postnatally; the melanocortin receptor blockade can alter leptin and anorexigenic effects in rats, leading to postnatal obesity (44).”
BackgroundStrader, A. D., Shi, H., Ogawa, R., Seeley, R. J., & Reizes, O. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.123091 · Cited by 10
“It is known that central administration of SHU9119 and -MSH affects insulin secretion (Adage et al., 2001; Obici et al., 2001).”
BackgroundInfluentialObesity pharmacology: past, present, and future
Kushner, R. F., & Manzano, H. (2002) · Current Opinion in Gastroenterology · doi:10.1097/00001574-200203000-00011 · Cited by 10
Melanocortin-4 receptor gene polymorphism and the level of physical activity in men (HALS Study)
Jóźków, P., Słowińska-Lisowska, M. R., Łaczmański, Ł., Jakubiec, D., & Medraś, M. (2010) · Endocrine · doi:10.1007/s12020-010-9412-7 · Cited by 8
“It has been also shown that administration of an antagonist of MC4R reduces spontaneous locomotor activity of rats [7].”
BackgroundGlucagon-Like Peptide-1 and Its Implications in Obesity
Hurtado-Carneiro, V., Roncero, I., Blázquez, E., Álvarez, E., & Sanz, C. (2013) · InTech eBooks · doi:10.5772/54221 · Cited by 9
“Thus, NPY increases food in‐ take and activates energy sparing mechanisms, while melanocortins decrease food intake and increase energy expenditure [56].”
BackgroundPhysical Activity: An Important Adaptative Mechanism for Body-Weight Control
Finelli, C., Gioia, S., & Sala, N. L. (2012) · ISRN Obesity · doi:10.5402/2012/675285 · Cited by 7
“Several animal studies show that the stimulation of the melanocortin-4 receptor (MC4R) is associated with an increase in spontaneous PhA [32, 33].”
RetractedLargent, B. L., Robichaud, A. J., & Miller, K. J. (2002) · Annual reports in medicinal chemistry · doi:10.1016/s0065-7743(02)37002-7 · Cited by 6
Neural regulation of cholesterol metabolism
Pérez–Tilve, D., Habegger, K. M., Tschöp, M. H., & Hofmann, S. M. (2011) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e328348a459 · Cited by 5
Sarvestani, F. S., Zare, M. A., Saki, F., Koohpeyma, F., Al-Abdullah, I. H., & Azarpira, N. (2020) · PubMed Central · doi:10.22038/ijbms.2019.39582.9387 · Cited by 5
Heinsbroek, A. C. M., & van Dijk, G. (2008) · International Journal of Obesity · doi:10.1038/ijo.2008.211 · Cited by 5
“8 A key network involved in the signalling of leptin is the brain melanocortin (MC) system”
BackgroundBASIC ENDOCRINE PRODUCTS OF ADIPOSE TISSUE - A REVIEW
Slavov, E., & Dzhelebov, P. (2010) · Bulgarian Portal for Open Science · Cited by 4
Székely, M., Balaskó, M., & Pétervári, E. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-385095-9.00257-8 · Cited by 3
Glucokinase as a Glucose Sensor in Hypothalamus - Regulation by Orexigenic and Anorexigenic Peptides
Sanz, C., Roncero, I., Álvarez, E., Hurtado-Carneiro, V., & Blázquez, E. (2011) · InTech eBooks · doi:10.5772/20826 · Cited by 2
“These neuropeptides have opposite effects on energy homeostasis, since NPY increases food intake and inhibit energy expenditure, while POMC exerts the contrary effects (Adage et al., 2001).”
BackgroundCNS regulation of plasma cholesterol
Pérez–Tilve, D., Davidson, W. S., Tschöp, M. H., & Hofmann, S. M. (2011) · Annals of Medicine · doi:10.3109/07853890.2011.590819 · Cited by 3
van Dijk, G., & Kas, M. J. (2014) · Cambridge University Press eBooks · doi:10.1017/9781107360556.005 · Cited by 2
Insights into 5-HT2C Receptor Function Gained from Transgenic Mouse Models
Bonasera, S. J. (2010) · The Receptors · doi:10.1007/978-1-60761-941-3_4 · Cited by 1
“The SCN core is densely innervated by both NPYergic and serotonergic fibers ( Abrahamson and Moore 2001 ) and strongly expresses 5-HT 2C Rs (in a manner largely complementary to arginine vasopressin [AVP] expression) (Hsu and Tecott LH in preparation).”
BackgroundBrain Melanocortin Receptors are Involved In CRH-Mediated HPA Axis Activity And Thermogenesis
de Vries, K. (2011) · The Open Neuroendocrinology Journal · doi:10.2174/1876528901104010127 · Cited by 1
“Data were considered significant if levels of p < 0.05.”
InfluentialNikhra, V. (2018) · Current Trends in Biomedical Engineering & Biosciences · doi:10.19080/ctbeb.2018.17.555960 · Cited by 1
“The activity of these neuropeptide systems is controlled by leptin, and possibly by melanocortins as well [30].”
BackgroundPéptidos anorexigénicos y su participación en la conducta alimentaria
Jaimes-Hoy, L., Cabrera‐Wrooman, A., Vilches‐Flores, A., Guzmán, C., & Arroyo, I. (2005) · Revista de Endocrinología y Nutrición · Cited by 1
Is Insulin Resistance a Disorder of the Brain?
Das, U. N. (2010) · doi:10.1002/9780813820637.ch5 · Cited by 1
“Hyperleptinemia also produced elevation of blood pressure and increased urinary catecholamine excretion that was abolished by alpha1-adrenergic, betaadrenergic, or ganglionic blockers suggesting that leptin stimulates sympathetic nervous system (18).”
BackgroundEating, the second best thing in life
Scheurink, A. J. W. (2006) · gedrag en gezondheid · doi:10.1007/bf03087981 · Cited by 1
Self-citation
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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