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 c...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 Rptorob−/−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 Rptorknockout osteoblasts.Collectively,these findings point to a critical role for the mTORC1 complex in the skeletal regulation of wholebody glucose metabolism and the skeletal development of insulin resistance.展开更多
基金the National Health and Medical Research Council of Australia(APP1109207,awarded to ACWZ,PMB,and CGP)Australian Research Council(DP160100454,awarded to ACWZ and PMB)+1 种基金Diabetes Australia Research Program(awarded to ACWZ,SF and SM)an Australia Postgraduate Award(PT).
文摘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 Rptorob−/−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 Rptorknockout osteoblasts.Collectively,these findings point to a critical role for the mTORC1 complex in the skeletal regulation of wholebody glucose metabolism and the skeletal development of insulin resistance.
