Nature Communications (Oct 2024)

Targeting osteoblastic 11β-HSD1 to combat high-fat diet-induced bone loss and obesity

  • Chuanxin Zhong,
  • Nanxi Li,
  • Shengzheng Wang,
  • Dijie Li,
  • Zhihua Yang,
  • Lin Du,
  • Guangxin Huang,
  • Haitian Li,
  • Wing Sze Yeung,
  • Shan He,
  • Shuting Ma,
  • Zhuqian Wang,
  • Hewen Jiang,
  • Huarui Zhang,
  • Zhanghao Li,
  • Xiaoxin Wen,
  • Song Xue,
  • Xiaohui Tao,
  • Haorui Li,
  • Duoli Xie,
  • Yihao Zhang,
  • Zefeng Chen,
  • Junqin Wang,
  • Jianfeng Yan,
  • Zhengming Liang,
  • Zongkang Zhang,
  • Zhigang Zhong,
  • Zeting Wu,
  • Chao Wan,
  • Chao Liang,
  • Luyao Wang,
  • Sifan Yu,
  • Yuan Ma,
  • Yuanyuan Yu,
  • Fangfei Li,
  • Yang Chen,
  • Baoting Zhang,
  • Aiping Lyu,
  • Fuzeng Ren,
  • Hong Zhou,
  • Jin Liu,
  • Ge Zhang

DOI
https://doi.org/10.1038/s41467-024-52965-4
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 18

Abstract

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Abstract Excessive glucocorticoid (GC) action is linked to various metabolic disorders. Recent findings suggest that disrupting skeletal GC signaling prevents bone loss and alleviates metabolic disorders in high-fat diet (HFD)-fed obese mice, underpinning the neglected contribution of skeletal GC action to obesity and related bone loss. Here, we show that the elevated expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), the enzyme driving local GC activation, and GC signaling in osteoblasts, are associated with bone loss and obesity in HFD-fed male mice. Osteoblast-specific 11β-HSD1 knockout male mice exhibit resistance to HFD-induced bone loss and metabolic disorders. Mechanistically, elevated 11β-HSD1 restrains glucose uptake and osteogenic activity in osteoblast. Pharmacologically inhibiting osteoblastic 11β-HSD1 by using bone-targeted 11β-HSD1 inhibitor markedly promotes bone formation, ameliorates glucose handling and mitigated obesity in HFD-fed male mice. Taken together, our study demonstrates that osteoblastic 11β-HSD1 directly contributes to HFD-induced bone loss, glucose handling impairment and obesity.