Overnutrition causes hyperactivation of mTORC1-dependent negative feedback loops leading to the downregulation of insulin signaling and development of insulin resistance. In osteoblasts (OBs), insulin signaling plays a crucial role in the control of systemic glucose homeostasis. We utilized mice with conditional deletion of Rptor to investigate how the loss of mTORC1 function in OB affects glucose metabolism under normal and overnutrition dietary states. Compared to the controls, chow-fed Rptor_ob^−/− mice had substantially less fat mass and exhibited adipocyte hyperplasia. Remarkably, upon feeding with high-fat diet, mice with pre- and post-natal deletion of Rptor in OBs were protected from diet-induced obesity and exhibited improved glucose metabolism with lower fasting glucose and insulin levels, increased glucose tolerance and insulin sensitivity. This leanness and resistance to weight gain was not attributable to changes in food intake, physical activity or lipid absorption but instead was due to increased energy expenditure and greater whole-body substrate flexibility. RNA-seq revealed an increase in glycolysis and skeletal insulin signaling pathways, which correlated with the potentiation of insulin signaling and increased insulin-dependent glucose uptake in Rptor-knockout osteoblasts. Collectively, these findings point to a critical role for the mTORC1 complex in the skeletal regulation of whole-body glucose metabolism and the skeletal development of insulin resistance.

营养过剩会导致mTORC1依赖性负反馈回路过度激活，从而导致胰岛素信号下调和胰岛素抵抗的发展。在成骨细胞（OBs）中，胰岛素信号传导在控制全身性葡萄糖稳态中起着至关重要的作用。我们利用条件性删除Rptor的小鼠来研究OB中mTORC1功能的丧失如何影响正常和营养过度饮食状态下的葡萄糖代谢。与对照组相比，用食物喂养的Rptor _ob ^-/-小鼠的脂肪量少得多，并且脂肪细胞增生。值得注意的是，高脂饮食喂养后，出生前和出生后Rptor缺失的小鼠OBs的饮食可以防止饮食引起的肥胖，并且空腹血糖和胰岛素水平降低，葡萄糖代谢改善，葡萄糖耐量和胰岛素敏感性提高。这种瘦弱和对体重增加的抵抗力不归因于食物摄入，身体活动或脂质吸收的变化，而是归因于增加的能量消耗和更大的全身底物柔韧性。RNA-seq显示糖酵解和骨骼胰岛素信号转导通路增加，这与Rptor中的胰岛素信号转导增强和胰岛素依赖性葡萄糖摄取增加有关-敲除成骨细胞。这些发现共同表明，mTORC1复合物在全身葡萄糖代谢的骨骼调节和胰岛素抵抗的骨骼发育中起着关键作用。