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

Cell Rep. 2025 Feb 25;44(2):115277. doi: 10.1016/j.celrep.2025.115277. Epub 2025 Feb 12.

Abstract

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.

Keywords: CP: Neuroscience; MCH neurons; insulin sensitivity; lateral hypothalamus; obesity; orexin; orexin receptor; sleep regulation.

MeSH terms

  • Animals
  • Female
  • Hypothalamic Hormones* / metabolism
  • Insulin Resistance* / physiology
  • Melanins* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neurons* / metabolism
  • Orexin Receptors* / genetics
  • Orexin Receptors* / metabolism
  • Orexins / metabolism
  • Pituitary Hormones* / metabolism
  • Signal Transduction*
  • Sleep, REM* / physiology

Substances

  • melanin-concentrating hormone
  • Melanins
  • Pituitary Hormones
  • Hypothalamic Hormones
  • Orexin Receptors
  • Orexins