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

Shuntaro Izawa1, Debora Fusca2, Hong Jiang3

  • 1Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany.

Cell Reports
|February 13, 2025
PubMed

Insights

Orexin/hypocretin receptor type 2 (Ox2R) in melanin-concentrating hormone (MCH) neurons impacts sleep and metabolism. Ox2R inactivation in MCH neurons disrupts sleep transitions and impairs metabolic regulation in female mice.

Area of Science:

  • Neuroscience
  • Endocrinology
  • Sleep Medicine

Background:

  • Orexin/hypocretin receptor type 2 (Ox2R) is crucial for regulating sleep and metabolism.
  • Ox2R selective agonists are being developed for narcolepsy treatment.
  • Melanin-concentrating hormone (MCH) neurons have opposing roles to orexin neurons in sleep and metabolism.

Purpose of the Study:

  • To investigate the expression and function of Ox2R in MCH neurons.
  • To understand how Ox2R signaling in MCH neurons influences sleep-wake cycles and metabolic processes.
  • To explore the heterogeneity of Ox2R-expressing MCH neurons.

Main Methods:

  • Analysis of RNA expression in Ox2R-expressing MCH neurons.
  • Electrophysiological recordings in brain slices to assess orexin B effects on MCH neurons.
  • Genetic inactivation of Ox2R in MCH neurons in female mice.
  • Assessment of sleep patterns (NREM/REM transitions) and metabolic parameters (insulin sensitivity, feeding behavior).

Main Results:

  • Ox2R-expressing MCH neurons exhibit heterogeneous RNA expression.
  • Orexin B elicits both excitatory and inhibitory responses in distinct MCH neuron populations.
  • Ox2R inactivation in MCH neurons reduced NREM to REM sleep transitions.
  • Impaired insulin sensitivity and excessive feeding were observed after Ox2R inactivation in MCH neurons in female mice.

Conclusions:

  • Ox2R plays a dual role (excitatory and inhibitory) in MCH neuron sub-populations.
  • Ox2R signaling within MCH neurons is vital for regulating sleep architecture and metabolic homeostasis in female mice.
Keywords:
CP: NeuroscienceMCH neuronsinsulin sensitivitylateral hypothalamusobesityorexinorexin receptorsleep regulation

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