Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.
Department of Materials Science and Engineering, Southern University of Science and Technology, Shenzhen, Guangdong, China.
Nat Commun. 2024 Oct 4;15(1):8588. doi: 10.1038/s41467-024-52965-4.
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.
过量的糖皮质激素（GC）作用与各种代谢紊乱有关。最近的研究结果表明，破坏骨骼 GC 信号可防止高脂肪饮食（HFD）喂养肥胖小鼠的骨丢失并减轻代谢紊乱，这突显了骨骼 GC 作用对肥胖和相关骨丢失的被忽视的贡献。在这里，我们表明，11β-羟类固醇脱氢酶 1 型（11β-HSD1）的表达升高，该酶可驱动局部 GC 激活，以及成骨细胞中的 GC 信号，与 HFD 喂养雄性小鼠的骨丢失和肥胖有关。成骨细胞特异性 11β-HSD1 敲除雄性小鼠对 HFD 诱导的骨丢失和代谢紊乱具有抗性。从机制上讲，升高的 11β-HSD1 抑制成骨细胞中的葡萄糖摄取和成骨活性。通过使用骨靶向 11β-HSD1 抑制剂抑制成骨细胞中的 11β-HSD1 可显著促进骨形成，改善 HFD 喂养雄性小鼠的葡萄糖处理能力并减轻肥胖。综上所述，我们的研究表明，成骨细胞 11β-HSD1 直接导致 HFD 诱导的骨丢失、葡萄糖处理受损和肥胖。
