Obesity-Associated Hypermetabolism and Accelerated Senescence of Bone Marrow Stromal Stem Cells Suggest a Potential Mechanism for Bone Fragility

Summary: Obesity is associated with increased risk for fragility fractures. However, the cellular mechanisms are unknown. Using a translational approach combining RNA sequencing and cellular analyses, we investigated bone marrow stromal stem cells (BM-MSCs) of 54 men divided into lean, overweight, and obese groups on the basis of BMI. Compared with BM-MSCs obtained from lean, obese BM-MSCs exhibited a shift of molecular phenotype toward committed adipocytic progenitors and increased expression of metabolic genes involved in glycolytic and oxidoreductase activity. Interestingly, compared with paired samples of peripheral adipose tissue-derived stromal cells (AT-MSCs), insulin signaling of obese BM-MSCs was enhanced and accompanied by increased abundance of insulin receptor positive (IR+) and leptin receptor positive (LEPR+) cells in BM-MSC cultures. Their hyper-activated metabolic state was accompanied by an accelerated senescence phenotype. Our data provide a plausible explanation for the bone fragility in obesity caused by enhanced insulin signaling leading to accelerated metabolic senescence of BM-MSCs. : Tencerova et al. show that in human obesity, BM-MSCs exhibit a hypermetabolic state defined by upregulation of insulin signaling with enhanced adipogenesis and increased intracellular reactive oxygen species (ROS), leading to a senescence bone microenvironment contributing to bone fragility. Moreover, increased abundance of IR+ and LEPR+ BM-MSCs is characteristic of this phenotype, with an activated metabolic rate in obese subjects. Keywords: obesity, skeletal fragility, bone marrow skeletal stem cells, adipose-derived stem cells, differentiation potential, adipogenesis, insulin signalin