Abstract
ABSTRACTThe mammalian target of rapamycin complex 1 (mTORC1) complex is the major nutrient sensor in mammalian cells that responds to amino acids, energy levels, growth factors, and hormones, such as insulin, to control anabolic and catabolic processes. We have recently shown that suppression of the mTORC1 complex in bone‐forming osteoblasts (OBs) improved glucose handling in male mice fed a normal or obesogenic diet. Mechanistically, this occurs, at least in part, by increasing OB insulin sensitivity leading to upregulation of glucose uptake and glycolysis. Given previously reported sex‐dependent differences observed upon antagonism of mTORC1 signaling, we investigated the metabolic and skeletal effects of genetic inactivation of preosteoblastic‐mTORC1 in female mice. Eight‐week‐old control diet (CD)‐fed Rptor ob −/− mice had a low bone mass with a significant reduction in trabecular bone volume and trabecular number, reduced cortical bone thickness, and increased marrow adiposity. Despite no changes in body composition, CD‐fed Rptor ob −/− mice exhibited significant lower fasting insulin and glucose levels and increased insulin sensitivity. Upon high‐fat diet (HFD) feeding, Rptor ob −/− mice were resistant to a diet‐induced increase in whole‐body and total fat mass and protected from the development of diet‐induced insulin resistance. Notably, although 12 weeks of HFD increased marrow adiposity, with minimal changes in both trabecular and cortical bone in the female control mice, marrow adiposity was significantly reduced in HFD‐fed Rptor ob −/− compared to both HFD‐fed control and CD‐fed Rptor ob −/− mice. Collectively, our results demonstrate that mTORC1 function in preosteoblasts is crucial for skeletal development and skeletal regulation of glucose homeostasis in both male and female mice. Importantly, loss of mTORC1 function in OBs results in metabolic and physiological adaptations that mirror a caloric restriction phenotype (under CD) and protects against HFD‐induced obesity, associated insulin resistance, and marrow adiposity expansion. These results highlight the critical contribution of the skeleton in the regulation of whole‐body energy homeostasis. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Highlights
D ysregulated insulin signaling and the development of insulin insensitivity are common features of many chronic disorders including obesity, diabetes, and heart disease.[1]
Mass in animals fed a normal diet,(23,24) while overexpression or downregulation of INSR in OBs results in profound changes in systemic glucose metabolism in response to an obesogenic diet.[25,26] Consistent with these observations, we recently showed that suppression of the mammalian target of rapamycin complex 1 (mTORC1) complex in pre-OB improved glucose handling in male mice fed a normal or high-fat diet (HFD), at least in part, through an increase in OB insulin sensitivity leading to upregulation of glucose uptake and glycolysis.[27]. Given the sexually dimorphic effects observed upon reduced mTORC1 signaling in other studies, we investigated the effects of genetic inactivation of preosteoblastic mTORC1 (OB-mTORC1) in female mice
We have investigated the function of mTORC1 in skeletal development, osteoblast-mediated B cell development, and skeletal control of glucose homeostasis using male mice with conditional deletion of Rptor, an essential component of mTORC1, in pre-OBs (Rptorob−/− mice).(27,31,34) In our most recent study, we showed that suppression of the mTORC1 complex in OBs improved glucose handling in male mice fed a control diet (CD) or high-fat diet (HFD), at least in part, by increasing OB insulin sensitivity leading to upregulation of glucose uptake and glycolysis.[27]. To determine if this important observation was sex-dependent, female Rptorob−/− mice were fed a CD and assessments of bone phenotype and glucose metabolism were examined
Summary
D ysregulated insulin signaling and the development of insulin insensitivity are common features of many chronic disorders including obesity, diabetes, and heart disease.[1]. Multiple nutrient signals independently stimulate the mTORC1 pathway (reviewed in Ali et al[10]). These include amino acids, in particular the branched chain amino acid leucine (BCAAs), via Ras-related small GTP binding protein (RAG) guanosine triphosphatase (GTPase)-dependent signaling.[11] mTORC1 activity is stimulated by glucose and fatty acids through cellular energy status. Insulin signaling in osteoblasts (OBs), is necessary for whole-body glucose homeostasis, whereby OBspecific deletion of INSR (INSROB−/−) causes elevated blood glucose, increased insulin resistance, and increased peripheral fat n 2 of 14 TANGSEEFA ET AL
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
