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Orexin receptors 1 and 2 in serotonergic neurons differentially regulate peripheral glucose metabolism in obesity

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Listed:
  • Xing Xiao

    (Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism
    University Hospital Cologne
    University of Cologne)

  • Gagik Yeghiazaryan

    (University of Cologne
    University of Cologne)

  • Simon Hess

    (University of Cologne
    University of Cologne)

  • Paul Klemm

    (Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism
    University Hospital Cologne
    University of Cologne)

  • Anna Sieben

    (Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism
    University Hospital Cologne
    University of Cologne)

  • André Kleinridders

    (Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism
    University Hospital Cologne
    University of Cologne
    National Center for Diabetes Research (DZD))

  • Donald A. Morgan

    (University of Iowa, Carver College of Medicine)

  • F. Thomas Wunderlich

    (Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism
    University Hospital Cologne
    University of Cologne)

  • Kamal Rahmouni

    (University of Iowa, Carver College of Medicine)

  • Dong Kong

    (Boston Children’s Hospital and Harvard Medical School
    Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Thomas E. Scammell

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Bradford B. Lowell

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Peter Kloppenburg

    (University of Cologne
    University of Cologne)

  • Jens C. Brüning

    (Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism
    University Hospital Cologne
    University of Cologne
    National Center for Diabetes Research (DZD))

  • A. Christine Hausen

    (Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism
    University Hospital Cologne
    University of Cologne)

Abstract

The wake-active orexin system plays a central role in the dynamic regulation of glucose homeostasis. Here we show orexin receptor type 1 and 2 are predominantly expressed in dorsal raphe nucleus-dorsal and -ventral, respectively. Serotonergic neurons in ventral median raphe nucleus and raphe pallidus selectively express orexin receptor type 1. Inactivation of orexin receptor type 1 in serotonin transporter-expressing cells of mice reduced insulin sensitivity in diet-induced obesity, mainly by decreasing glucose utilization in brown adipose tissue and skeletal muscle. Selective inactivation of orexin receptor type 2 improved glucose tolerance and insulin sensitivity in obese mice, mainly through a decrease in hepatic gluconeogenesis. Optogenetic activation of orexin neurons in lateral hypothalamus or orexinergic fibers innervating raphe pallidus impaired or improved glucose tolerance, respectively. Collectively, the present study assigns orexin signaling in serotonergic neurons critical, yet differential orexin receptor type 1- and 2-dependent functions in the regulation of systemic glucose homeostasis.

Suggested Citation

  • Xing Xiao & Gagik Yeghiazaryan & Simon Hess & Paul Klemm & Anna Sieben & André Kleinridders & Donald A. Morgan & F. Thomas Wunderlich & Kamal Rahmouni & Dong Kong & Thomas E. Scammell & Bradford B. Lo, 2021. "Orexin receptors 1 and 2 in serotonergic neurons differentially regulate peripheral glucose metabolism in obesity," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25380-2
    DOI: 10.1038/s41467-021-25380-2
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    Cited by:

    1. Roberto Luca & Stefano Nardone & Kevin P. Grace & Anne Venner & Michela Cristofolini & Sathyajit S. Bandaru & Lauren T. Sohn & Dong Kong & Takatoshi Mochizuki & Bianca Viberti & Lin Zhu & Antonino Zit, 2022. "Orexin neurons inhibit sleep to promote arousal," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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