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

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.

Pathophysiology of obesity and its associated diseases

The occurrence of obesity has increased across the whole world. Many epidemiological studies have indicated that obesity strongly contributes to the development of cancer, cardiovascular diseases, type 2 diabetes, liver diseases and other disorders, accounting for a heavy burden on the public and on health-care systems every year. Excess energy uptake induces adipocyte hypertrophy, hyperplasia and formation of visceral fat in other non-adipose tissues to evoke cardiovascular disease, liver diseases. Adipose tissue can also secrete adipokines and inflammatory cytokines to affect the local microenvironment,induce insulin resistance, hyperglycemia, and activate associated inflammatory signaling pathways. This further exacerbates the development and progression of obesity-associated diseases. Although some progress in the treatment of obesity has been achieved in preclinical and clinical studies, the progression and pathogenesis of obesity-induced diseases are complex and unclear. We still need to understand their links to better guide the treatment of obesity and associated diseases. In this review, we review the links between obesity and other diseases, with a view to improve the future management and treatment of obesity and its co-morbidities.

A high-throughput screening assay for eukaryotic elongation factor 2 kinase inhibitors

Eukaryotic elongation factor 2 kinase (eEF2K) inhibitors may aid in the development of new therapeutic agents to combat cancer. Purified human eEF2K was obtained from an Escherichia coli expression system and a luminescence-based high-throughput screening (HTS) assay was developed using MH-1 peptide as the substrate. The luminescent readouts correlated with the amount of adenosine triphosphate remaining in the kinase reaction. This method was applied to a large-scale screening campaign against a diverse compound library and subsequent confirmation studies. Nine initial hits showing inhibitory activities on eEF2K were identified from 56,000 synthetic compounds during the HTS campaign, of which, five were chosen to test their effects in cancer cell lines. (C) 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND

mTORC1 signaling:what we still don’t know

The mammalian target of rapamycin(mTOR)is a protein kinase that plays key roles in cellular regulation.It forms complexes with additional proteins.The best-understood one is mTOR complex 1(mTORC1).The regulation and cellular functions of mTORC1 have been the subjects of intense study;despite this,many questions remain to be answered.They include questions about the actual mechanisms by which mTORC1 signaling is stimulated by hormones and growth factors,which involves the small GTPase Rheb,and by amino acids,which involves other GTPase proteins.The control of Rheb and the mechanism by which it activates mTORC1 remain incompletely understood.Although it has been known for many years that rapamycin interferes with some functions of mTORC1,it is not known how it does this,or why only some functions of mTORC1 are affected.mTORC1 regulates diverse cellular functions.Several mTORC1 substrates are now known,although in several cases their physiological roles are poorly or incompletely understood.In the case of several processes,although it is clear that they are regulated by mTORC1,it is not known how mTORC1 does this.Lastly,mTORC1 is implicated in ageing,but again it is unclear what mechanisms account for this.Given the importance of mTORC1 signaling both for cellular functions and in human disease,it is a high priority to gain further insights into the control of mTORC1 signaling and the mechanisms by which it controls cellular functions and animal physiology.