Skeleton interoception regulates bone and fat metabolism through hypothalamic neuroendocrine NPY

Xiao Lv; Feng Gao; Tuo Peter Li; Peng Xue; Xiao Wang; Mei Wan; Bo Hu; Hao Chen; Amit Jain; Zengwu Shao; Xu Cao

doi:10.7554/eLife.70324

eLife (Sep 2021)

Skeleton interoception regulates bone and fat metabolism through hypothalamic neuroendocrine NPY

Xiao Lv,
Feng Gao,
Tuo Peter Li,
Peng Xue,
Xiao Wang,
Mei Wan,
Bo Hu,
Hao Chen,
Amit Jain,
Zengwu Shao,
Xu Cao

Affiliations

Xiao Lv: ORCiD; Department of Orthopaedic Surgery, Institute of Cell Engineering, and Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, United States; Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Feng Gao: Department of Orthopaedic Surgery, Institute of Cell Engineering, and Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, United States; Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Tuo Peter Li: ORCiD; Department of Orthopaedic Surgery, Institute of Cell Engineering, and Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, United States
Peng Xue: Department of Orthopaedic Surgery, Institute of Cell Engineering, and Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, United States
Xiao Wang: ORCiD; Department of Orthopaedic Surgery, Institute of Cell Engineering, and Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, United States
Mei Wan: ORCiD; Department of Orthopaedic Surgery, Institute of Cell Engineering, and Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, United States
Bo Hu: Department of Orthopaedic Surgery, Institute of Cell Engineering, and Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, United States
Hao Chen: Department of Orthopaedic Surgery, Institute of Cell Engineering, and Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, United States
Amit Jain: Department of Orthopaedic Surgery, Institute of Cell Engineering, and Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, United States
Zengwu Shao: Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Xu Cao: ORCiD; Department of Orthopaedic Surgery, Institute of Cell Engineering, and Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, United States

DOI: https://doi.org/10.7554/eLife.70324
Journal volume & issue: Vol. 10

Abstract

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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.

Published in eLife

ISSN: 2050-084X (Online)
Publisher: eLife Sciences Publications Ltd
Country of publisher: United Kingdom
LCC subjects: Medicine; Science: Biology (General)
Website: https://elifesciences.org

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