High fat diet induces specific pathological changes in hypothalamic orexin neurons in mice.

Loss of orexin neurons in the hypothalamus is a prominent feature of narcolepsy and several other neurological conditions. We have recently demonstrated that sleep deprivation stimulates local nitric oxide (NO) production by neuronal NO synthase in the lateral hypothalamus, which leads to selective degeneration of orexin neurons accompanied by formation of orexin-immunoreactive aggregates. Here we analyzed whether lifestyle-related conditions other than sleep deprivation could trigger similar pathological changes in orexin neurons. Four-week-old male C57BL/6 mice were fed with high fat diet (HFD) for 8 weeks. Immunohistochemical analysis revealed that the number of orexin-immunopositive neurons was significantly decreased by HFD intake, whereas the number of melanin-concentrating hormone-immunopositive neurons was unchanged. In addition, HFD promoted formation of intracellular orexin-immunoreactive aggregates in a subset of orexin neurons. We also confirmed that expression of inducible NO synthase (iNOS) in the hypothalamus was upregulated in response to HFD intake. Notably, loss of orexin-immunopositive neurons and formation of orexin-immunoreactive aggregates were not observed in iNOS knockout mice fed with HFD. These results indicate that inappropriate dietary conditions could trigger specific neuropathological events in orexin neurons in an iNOS-dependent manner.