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

Research output: Contribution to journalArticle

18 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)927-940
Number of pages14
JournalCell Metabolism
Issue number6
StatePublished - Jun 3 2014


ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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