Skeleton interoception regulates bone and fat metabolism through hypothalamic neuroendocrine NPY

  1. Xiao Lv
  2. Feng Gao
  3. Tuo Peter Li
  4. Peng Xue
  5. Xiao Wang
  6. Mei Wan
  7. Bo Hu
  8. Hao Chen
  9. Amit Jain
  10. Zengwu Shao
  11. Xu Cao  Is a corresponding author
  1. Johns Hopkins University School of Medicine, United States
  2. Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China

Abstract

The central nervous system regulates activity of peripheral organs through interoception. In our previous study, we have demonstrated that PGE2/EP4 skeleton interception regulate bone homeostasis. Here we show that ascending skeleton interoceptive signaling downregulates expression of hypothalamic neuropeptide Y (NPY) and induce lipolysis of adipose tissue for osteoblastic bone formation. Specifically, the ascending skeleton interoceptive signaling induces expression of small heterodimer partner-interacting leucine zipper protein (SMILE) in the hypothalamus. SMILE binds to pCREB as a transcriptional heterodimer on Npy promoters to inhibit NPY expression. Knockout of EP4 in sensory nerve increases expression of NPY causing bone catabolism and fat anabolism. Importantly, inhibition of NPY Y1 receptor (Y1R) accelerated oxidation of free fatty acids in osteoblasts and rescued bone loss in AvilCre:Ptger4fl/fl mice. Thus, downregulation of hypothalamic NPY expression lipolyzes free fatty acids for anabolic bone formation through a neuroendocrine descending interoceptive regulation.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1-7.

Article and author information

Author details

  1. Xiao Lv

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0175-5240
  2. Feng Gao

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Tuo Peter Li

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4302-9538
  4. Peng Xue

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Xiao Wang

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6395-706X
  6. Mei Wan

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9404-540X
  7. Bo Hu

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Hao Chen

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Amit Jain

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Zengwu Shao

    Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Xu Cao

    Johns Hopkins University School of Medicine, Baltimore, United States
    For correspondence
    xcao11@jhmi.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8614-6059

Funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (MO18M298) of the Johns Hopkins University.

Reviewing Editor

  1. Mone Zaidi, Department of Medicine, Icahn School of Medicine at Mount Sinai, United States

Publication history

  1. Received: May 13, 2021
  2. Accepted: May 21, 2021
  3. Accepted Manuscript published: September 1, 2021 (version 1)
  4. Version of Record published: September 14, 2021 (version 2)
  5. Version of Record updated: January 3, 2023 (version 3)

Copyright

© 2021, Lv et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Xiao Lv
  2. Feng Gao
  3. Tuo Peter Li
  4. Peng Xue
  5. Xiao Wang
  6. Mei Wan
  7. Bo Hu
  8. Hao Chen
  9. Amit Jain
  10. Zengwu Shao
  11. Xu Cao
(2021)
Skeleton interoception regulates bone and fat metabolism through hypothalamic neuroendocrine NPY
eLife 10:e70324.
https://doi.org/10.7554/eLife.70324

Further reading

    1. Medicine
    2. Neuroscience
    Yuanshu Chen, Haochen Zou ... Keith M Kendrick
    Research Article Updated

    Background:

    Social touch constitutes a key component of human social relationships, although in some conditions with social dysfunction, such as autism, it can be perceived as unpleasant. We have previously shown that intranasal administration of oxytocin facilitates the pleasantness of social touch and activation of brain reward and social processing regions, although it is unclear if it influences responses to gentle stroking touch mediated by cutaneous C-touch fibers or pressure touch mediated by other types of fibers. Additionally, it is unclear whether endogenous oxytocin acts via direct entry into the brain or by increased peripheral blood concentrations.

    Methods:

    In a randomized controlled design, we compared effects of intranasal (direct entry into the brain and increased peripheral concentrations) and oral (only peripheral increases) oxytocin on behavioral and neural responses to social touch targeting C-touch (gentle-stroking) or other (medium pressure without stroking) cutaneous receptors.

    Results:

    Although both types of touch were perceived as pleasant, intranasal and oral oxytocin equivalently enhanced pleasantness ratings and responses of reward, orbitofrontal cortex, and social processing, superior temporal sulcus, regions only to gentle-stroking not medium pressure touch. Furthermore, increased blood oxytocin concentrations predicted the pleasantness of gentle stroking touch. The specificity of neural effects of oxytocin on C-touch targeted gentle stroking touch were confirmed by time-course extraction and classification analysis.

    Conclusions:

    Increased peripheral concentrations of oxytocin primarily modulate its behavioral and neural responses to gentle social touch mediated by C-touch fibers. Findings have potential implications for using oxytocin therapeutically in conditions where social touch is unpleasant.

    Funding:

    Key Technological Projects of Guangdong Province grant 2018B030335001.

    Clinical trial number:

    NCT05265806