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

Area of Science:

• Neuroscience
• Metabolic Research
• Neuropathology

Background:

• Loss of orexin neurons is a hallmark of narcolepsy and other neurological disorders.
• Sleep deprivation induces nitric oxide (NO) production, leading to orexin neuron degeneration and aggregate formation.

Purpose of the Study:

• To investigate if lifestyle factors beyond sleep deprivation, specifically high-fat diet (HFD), can induce similar pathological changes in orexin neurons.
• To elucidate the role of inducible nitric oxide synthase (iNOS) in HFD-induced orexin neuron damage.

Main Methods:

• Four-week-old male C57BL/6 mice were fed a high-fat diet (HFD) for 8 weeks.
• Immunohistochemical analysis was used to quantify orexin- and melanin-concentrating hormone-immunopositive neurons.
• Expression of inducible nitric oxide synthase (iNOS) was analyzed.
• Experiments were repeated using iNOS knockout mice fed an HFD.

Main Results:

• HFD intake significantly decreased the number of orexin-immunopositive neurons, while melanin-concentrating hormone neurons remained unaffected.
• HFD promoted the formation of intracellular orexin-immunoreactive aggregates.
• Expression of iNOS in the hypothalamus was upregulated by HFD.
• Loss of orexin neurons and aggregate formation were prevented in iNOS knockout mice fed an HFD.

Conclusions:

• Inappropriate dietary conditions, such as HFD, can trigger neuropathological events in orexin neurons.
• These diet-induced changes are dependent on inducible nitric oxide synthase (iNOS).
• This suggests a link between metabolic dysfunction and neurodegeneration in orexin systems.