Publications

Publications Search

Search for publications by author
Search for publications by abstract keyword(s)

The mTORC1 complex in pre-osteoblasts regulates whole-body energy metabolism independently of osteocalcin

Abstract

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 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.

Type Journal
ISBN 2095-4700 (Print) 2095-4700 (Linking)
Authors Tangseefa, P.; Martin, S. K.; Chin, P. Y.; Breen, J.; Mah, C. Y.; Baldock, P. A.; Wittert, G. A.; Page, A. J.; Proud, C. G.; Fitter, S.; Zannettino, A. C. W.
Responsible Garvan Author Associate Professor Paul Baldock
Publisher Name Bone Research
Published Date 2021-02-28
Published Volume 9
Published Issue 1
Published Pages 10
Status Published in-print
DOI 10.1038/s41413-020-00123-z
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/33551450