Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity.
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.
Horvath
Tamas L
TL
Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Sarman
Beatrix
B
García-Cáceres
Cristina
C
Enriori
Pablo J
PJ
Sotonyi
Peter
P
Shanabrough
Marya
M
Borok
Erzsebet
E
Argente
Jesus
J
Chowen
Julie A
JA
Perez-Tilve
Diego
D
Pfluger
Paul T
PT
Brönneke
Hella S
HS
Levin
Barry E
BE
Diano
Sabrina
S
Cowley
Michael A
MA
Tschöp
Matthias H
MH
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
D004041:Dietary Fats; D053486:Melanocortins; D009478:Neuropeptide Y; D011333:Pro-Opiomelanocortin