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

Tamas L Horvath, Beatrix Sarman, Cristina Garcia-Caceres, Pablo Enriori, Peter Sotonyi, Marya Shanabrough, Erzsebet Borok, Jesus Argente, Julie A Chowen, Diego Perez-Tilve, Paul T Pfluger, Hella S Bronneke, Barry E Levin, Sabrina Diano, Michael A Cowley, Matthias H Tschop

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257 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)14875 - 14880
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number33
Publication statusPublished - 2010

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