Orexin/hypocretin receptor 2 signaling in MCH neurons regulates REM sleep and insulin sensitivity.

Orexin/hypocretin receptor type 2 (Ox2R), which is widely expressed in the brain, receives orexin signals and modulates sleep and metabolism. Ox2R selective agonists are currently under clinical trials for narcolepsy treatment. Here, we focused on Ox2R expression and function in melanin-concentrating hormone (MCH) neurons, which have opposite roles to orexin neurons in sleep and metabolism regulation. Ox2R-expressing MCH neurons showed heterogeneity of RNA expression, and orexin B application in brain slices induced both excitatory and inhibitory responses in distinct MCH neuron populations. Ox2R inactivation in MCH neurons reduced transitions from non-rapid eye movement (NREM) to REM sleep and impaired insulin sensitivity with excessive feeding after a fasting period in female mice. In conclusion, Ox2R mediates excitatory and inhibitory responses in MCH neuron sub-populations in vivo, which regulate sleep and metabolism in female mice.