title: Forebrain melanocortin signaling enhances the hindbrain satiety response to CCK-8.
abstract: Melanocortin 4 receptors (MC4R) are hypothesized to mediate the central nervous system actions of leptin to enhance the satiety effects of cholecystokinin (CCK). To further elucidate this mechanism, we confirmed that peripheral administration of CCK-8 is less effective in producing this effect in MC4R-deficient mice (MC4R(-/-)). Whereas intraperitoneal (ip) CCK-8 at 0.75 nmol/kg lean body mass (lbm) suppressed food intake in wild-type mice, CCK-8 doses of 7.5 nmol/kg lbm were required to attenuate food intake in MC4R(-/-) mice. To determine whether melanocortin signaling in the hypothalamic paraventricular nucleus (PVN) participates in regulating this CCK satiety response, we administered the MC3/MC4R antagonist, SHU9119, into the PVN of rats before ip CCK-8 administration. PVN administration of SHU9119 attenuated the ability of CCK-8 to reduce 30-min food intake by 20%. To determine whether MC4R are expressed by PVN neurons that project directly to hindbrain nuclei involved in the satiety response to ip CCK-8, the retrograde tracer fluorescent cholera toxin subunit B was injected into the nucleus tractus solitarius (NTS) of the hindbrain. After 4 days, labeled PVN neurons were collected by laser capture microdissection and found to express MC4R mRNA by quantitative RT-PCR analysis. These data provide evidence for a neuroanatomical link between hypothalamic melanocortin signaling in the PVN and NTS neurons that regulate food intake. These findings highlight the contribution of melanocortin signaling in the PVN toward regulating the satiety effects of CCK-8 while acknowledging that melanocortin-dependent pathways in other brain regions and/or melanocortin-independent mechanisms are also important in this mechanism.
authors.affiliation: VA Puget Sound Health Care System, Mail stop S-151, 1660 South Columbian Way, Seattle, WA 98108, USA. jeblevin@u.washington.edu
authors.forename: James E
authors.initials: JE
authors.lastname: Blevins
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Morton
authors.forename: Diana L
authors.initials: DL
authors.lastname: Williams
authors.forename: David W
authors.initials: DW
authors.lastname: Caldwell
authors.forename: Lloyd S
authors.initials: LS
authors.lastname: Bastian
authors.forename: Brent E
authors.initials: BE
authors.lastname: Wisse
authors.forename: Michael W
authors.initials: MW
authors.lastname: Schwartz
authors.forename: Denis G
authors.initials: DG
authors.lastname: Baskin
mesh_terms: D000818:Animals; D004435:Eating / Q000187:drug effects / Q000502:physiology; D020546:Fourth Ventricle / Q000502:physiology; D008297:Male; D053486:Melanocortins / Q000502:physiology*; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010286:Paraventricular Hypothalamic Nucleus / Q000502:physiology; D016548:Prosencephalon / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012249:Rhombencephalon / Q000187:drug effects*; D012528:Satiety Response / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*; D012844:Sincalide / Q000494:pharmacology*; D013238:Stereotaxic Techniques
chemical_list: D053486:Melanocortins; D012333:RNA, Messenger; D044105:Receptor, Melanocortin, Type 4; C103272:SHU 9119; D009074:Melanocyte-Stimulating Hormones; D012844:Sincalide