Orexin regulates bone remodeling via a dominant positive central action and a subordinate negative peripheral action

Wei Wei; Toshiyuki Motoike; Jing Y Krzeszinski; Zixue Jin; Xian-Jin Xie; Paul C Dechow; Masashi Yanagisawa; Yihong Wan

doi:10.1016/j.cmet.2014.03.016

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Orexin regulates bone remodeling via a dominant positive central action and a subordinate negative peripheral action

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Orexin regulates bone remodeling via a dominant positive central action and a subordinate negative peripheral action

Wei Wei, Toshiyuki Motoike, Jing Y Krzeszinski, Zixue Jin, Xian-Jin Xie, Paul C Dechow, Masashi Yanagisawa and Yihong Wan

Cell metabolism, Vol.19(6), pp.927-940

06/03/2014

DOI: 10.1016/j.cmet.2014.03.016

PMCID: PMC4047150

PMID: 24794976

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Abstract

Orexin neuropeptides promote arousal, appetite, reward, and energy expenditure. However, whether orexin affects bone mass accrual is unknown. Here, we show that orexin functions centrally through orexin receptor 2 (OX2R) in the brain to enhance bone formation. OX2R null mice exhibit low bone mass owing to elevated circulating leptin, whereas central administration of an OX2R-selective agonist augments bone mass. Conversely, orexin also functions peripherally through orexin receptor 1 (OX1R) in the bone to suppress bone formation. OX1R null mice exhibit high bone mass owing to a differentiation shift from marrow adipocyte to osteoblast that results from higher osseous ghrelin expression. The central action is dominant because bone mass is reduced in orexin null and OX1R2R double null mice but enhanced in orexin-overexpressing transgenic mice. These findings reveal orexin as a critical rheostat of skeletal homeostasis that exerts a yin-yang dual regulation and highlight orexin as a therapeutic target for osteoporosis.

Orexin Receptors - metabolism

Osteogenesis - physiology

Bone Density - physiology

Orexins

Mice, Inbred C57BL

Cells, Cultured

Neuropeptides - metabolism

Bone Density - genetics

Bone Remodeling - physiology

Intracellular Signaling Peptides and Proteins - metabolism

Ghrelin - biosynthesis

Mice, Knockout

Animals

Leptin - blood

RNA Interference

Orexin Receptors - agonists

Orexin Receptors - genetics

Mice, Obese

Mice

RNA, Small Interfering

Cell Differentiation - physiology

Details

Title: Subtitle: Orexin regulates bone remodeling via a dominant positive central action and a subordinate negative peripheral action
Creators: Wei Wei - Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Toshiyuki Motoike - The University of Texas Southwestern Medical Center
Jing Y Krzeszinski - Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Zixue Jin - Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Xian-Jin Xie - The University of Texas Southwestern Medical Center
Paul C Dechow - Department of Biomedical Sciences, Baylor College of Dentistry, Texas A&M University Health Sciences Center, Dallas, TX 75246, USA
Masashi Yanagisawa - The University of Texas Southwestern Medical Center
Yihong Wan - The University of Texas Southwestern Medical Center
Resource Type: Journal article
Publication Details: Cell metabolism, Vol.19(6), pp.927-940
Publisher: United States
DOI: 10.1016/j.cmet.2014.03.016
PMID: 24794976
PMCID: PMC4047150
ISSN: 1932-7420
eISSN: 1932-7420
Grant note: Howard Hughes Medical Institute R01 DK089113 / NIDDK NIH HHS R01DK089113 / NIDDK NIH HHS
Language: English
Date published: 06/03/2014
Academic Unit: Preventive and Community Dentistry; Biostatistics; Dental Research
Record Identifier: 9983917660402771

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