title: Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity.
abstract: The neuronal circuits involved in the regulation of feeding behavior and energy expenditure are soft-wired, reflecting the relative activity of the postsynaptic neuronal system, including the anorexigenic proopiomelanocortin (POMC)-expressing cells of the arcuate nucleus. We analyzed the synaptic input organization of the melanocortin system in lean rats that were vulnerable (DIO) or resistant (DR) to diet-induced obesity. We found a distinct difference in the quantitative and qualitative synaptology of POMC cells between DIO and DR animals, with a significantly greater number of inhibitory inputs in the POMC neurons in DIO rats compared with DR rats. When exposed to a high-fat diet (HFD), the POMC cells of DIO animals lost synapses, whereas those of DR rats recruited connections. In both DIO rats and mice, the HFD-triggered loss of synapses on POMC neurons was associated with increased glial ensheathment of the POMC perikarya. The altered synaptic organization of HFD-fed animals promoted increased POMC tone and a decrease in the stimulatory connections onto the neighboring neuropeptide Y (NPY) cells. Exposure to HFD was associated with reactive gliosis, and this affected the structure of the blood-brain barrier such that the POMC and NPY cell bodies and dendrites became less accessible to blood vessels. Taken together, these data suggest that consumption of an HFD has a major impact on the cytoarchitecture of the arcuate nucleus in vulnerable subjects, with changes that might be irreversible due to reactive gliosis.
authors.affiliation: Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Tamas L
authors.initials: TL
authors.lastname: Horvath
authors.forename: Beatrix
authors.initials: B
authors.lastname: Sarman
authors.forename: Cristina
authors.initials: C
authors.lastname: García-Cáceres
authors.forename: Pablo J
authors.initials: PJ
authors.lastname: Enriori
authors.forename: Peter
authors.initials: P
authors.lastname: Sotonyi
authors.forename: Marya
authors.initials: M
authors.lastname: Shanabrough
authors.forename: Erzsebet
authors.initials: E
authors.lastname: Borok
authors.forename: Jesus
authors.initials: J
authors.lastname: Argente
authors.forename: Julie A
authors.initials: JA
authors.lastname: Chowen
authors.forename: Diego
authors.initials: D
authors.lastname: Perez-Tilve
authors.forename: Paul T
authors.initials: PT
authors.lastname: Pfluger
authors.forename: Hella S
authors.initials: HS
authors.lastname: Brönneke
authors.forename: Barry E
authors.initials: BE
authors.lastname: Levin
authors.forename: Sabrina
authors.initials: S
authors.lastname: Diano
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cowley
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004032:Diet; D004041:Dietary Fats / Q000009:adverse effects; D005260:Female; D005911:Gliosis / Q000209:etiology / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D053486:Melanocortins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D009478:Neuropeptide Y / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D004041:Dietary Fats; D053486:Melanocortins; D009478:Neuropeptide Y; D011333:Pro-Opiomelanocortin