Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 33; pp. 14875 - 14880
• Main Authors: Horvath, Tamas L., Sarman, Beatrix, García-Cáceres, Cristina, Enriori, Pablo J., Sotonyi, Peter, Shanabrough, Marya, Borok, Erzsebet, Argente, Jesus, Chowen, Julie A., Perez-Tilve, Diego, Pfluger, Paul T., Brönneke, Hella S., Levin, Barry E., Diano, Sabrina, Cowley, Michael A., Tschöp, Matthias H., Friedman, Jeffrey M.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 17.08.2010; National Acad Sciences
• Subjects: Animals; Arcuate nucleus; Arcuate Nucleus of Hypothalamus - metabolism; Arcuate Nucleus of Hypothalamus - pathology; Arcuate Nucleus of Hypothalamus - physiopathology; Biological Sciences; Blood vessels; Blood-brain barrier; Body weight; Brain; Brain architecture; Cell body; Cells; Circuits; Data processing; Dendrites; Diet; Dietary Fats - adverse effects; Diets; Energy expenditure; Feeding behavior; Female; Gliosis; Gliosis - etiology; Gliosis - metabolism; High fat diet; Hypothalamus; Hypothalamus - metabolism; Hypothalamus - pathology; Hypothalamus - physiopathology; Immunohistochemistry; Male; Melanocortin; Melanocortins; Melanocortins - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Electron; Neuroglia; Neuronal-glial interactions; Neurons; Neurons - metabolism; Neurons - ultrastructure; Neuropeptide Y; Neuropeptide Y - metabolism; Obesity; Obesity - etiology; Obesity - metabolism; Peptides; pro-opiomelanocortin; Pro-Opiomelanocortin - metabolism; Proopiomelanocortin; Rats; Rats, Sprague-Dawley; Rodents; Synapses; Synapses - metabolism; Synaptic Transmission - physiology; vulnerability
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1004282107

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.