Chronic high-fat diet (HFD) consumption not only promotes obesity and insulin resistance, but also causes bone loss through mechanisms that are not well understood. Here, we fed wild-type CD-1 mice either chow or a HFD (43% of energy from fat) for 18 weeks; HFD-fed mice exhibited decreased trabecular volume (−28%) and cortical thickness (−14%) compared to chow-fed mice. In HFD-fed mice, bone loss was due to reduced bone formation and mineral apposition, without obvious effects on bone resorption. HFD feeding also increased skeletal expression of sclerostin and caused deterioration of the osteocyte lacunocanalicular network (LCN). In mice fed HFD, skeletal glucocorticoid signaling was activated relative to chow-fed mice, independent of serum corticosterone concentrations. We therefore examined whether skeletal glucocorticoid signaling was necessary for HFD-induced bone loss, using transgenic mice lacking glucocorticoid signaling in osteoblasts and osteocytes (HSD2^OB/OCY-tg mice). In HSD2^OB/OCY-tg mice, bone formation and mineral apposition rates were not suppressed by HFD, and bone loss was significantly attenuated. Interestingly, in HSD2^OB/OCY-tg mice fed HFD, both Wnt signaling (less sclerostin induction, increased β-catenin expression) and glucose uptake were significantly increased, relative to diet- and genotype-matched controls. The osteocyte LCN remained intact in HFD-fed HSD2^OB/OCY-tg mice. When fed a HFD, HSD2^OB/OCY-tg mice also increased their energy expenditure and were protected against obesity, insulin resistance, and dyslipidemia. Therefore, glucocorticoid signaling in osteoblasts and osteocytes contributes to the suppression of bone formation in HFD-fed mice. Skeletal glucocorticoid signaling is also an important determinant of glucose uptake in bone, which influences the whole-body metabolic response to HFD.

长期食用高脂肪饮食 (HFD) 不仅会促进肥胖和胰岛素抵抗，还会通过尚未完全了解的机制导致骨质流失。在这里，我们给野生型 CD-1 小鼠喂食食物或 HFD（43% 的能量来自脂肪）18 周；与饲料喂养的小鼠相比，HFD 喂养的小鼠表现出减少的小梁体积 (-28%) 和皮质厚度 (-14%)。在HFD喂养的小鼠中，骨质流失是由于骨形成和矿物质沉积减少，对骨吸收没有明显影响。HFD 喂养还增加了硬化蛋白的骨骼表达，并导致骨细胞腔隙网络 (LCN) 的恶化。在喂食 HFD 的小鼠中，骨骼糖皮质激素信号相对于饲料喂养的小鼠被激活，与血清皮质酮浓度无关。^OB/OCY-tg小鼠）。在 HSD2 ^{OB/OCY -tg}小鼠中，骨形成和矿物质沉积率不受 HFD 抑制，骨丢失显着减弱。有趣的是，在喂食 HFD 的HSD2 ^{OB/OCY -tg}小鼠中，相对于饮食和基因型匹配的对照，Wnt 信号传导（硬化蛋白诱导减少，β-连环蛋白表达增加）和葡萄糖摄取均显着增加。骨细胞LCN在HFD喂养的HSD2 ^OB/OCY - ^tg小鼠中保持完整。喂食 HFD 时，HSD2 ^OB/OCY-tg 小鼠还增加了它们的能量消耗，并免受肥胖、胰岛素抵抗和血脂异常的影响。因此，成骨细胞和骨细胞中的糖皮质激素信号有助于抑制 HFD 喂养小鼠的骨形成。骨骼糖皮质激素信号也是骨骼中葡萄糖摄取的重要决定因素，它影响全身对 HFD 的代谢反应。