Lipogenic effects of androgen signaling in normal and malignant prostate

Prostate cancer is an androgen-dependent cancer with unique metabolic features compared to many other solid tumors,and typically does not exhibit the“Warburg effect”.During malignant transformation,an early metabolic switch diverts the dependence of normal prostate cells on aerobic glycolysis for the synthesis of and secretion of citrate towards a more energetically favorable metabolic phenotype,whereby citrate is actively oxidised for energy and biosynthetic processes(i.e.de novo lipogenesis).It is now clear that lipid metabolism is one of the key androgen-regulated processes in prostate cells and alterations in lipid metabolism are a hallmark of prostate cancer,whereby increased de novo lipogenesis accompanied by overexpression of lipid metabolic genes are characteristic of primary and advanced disease.Despite recent advances in our understanding of altered lipid metabolism in prostate tumorigenesis and cancer progression,the intermediary metabolism of the normal prostate and its relationship to androgen signaling remains poorly understood.In this review,we discuss the fundamental metabolic relationships that are distinctive in normal versus malignant prostate tissues,and the role of androgens in the regulation of lipid metabolism at different stages of prostate tumorigenesis.

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.