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.

Reviewing Editor

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

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.

Version 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

Share this article

https://doi.org/10.7554/eLife.70324

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