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

• Published in: Cell reports (Cambridge) Vol. 27; no. 7; pp. 2050 - 2062.e6
• Main Authors: Tencerova, Michaela, Frost, Morten, Figeac, Florence, Nielsen, Tina Kamilla, Ali, Dalia, Lauterlein, Jens-Jacob Lindegaard, Andersen, Thomas Levin, Haakonsson, Anders Kristian, Rauch, Alexander, Madsen, Jonna Skov, Ejersted, Charlotte, Højlund, Kurt, Kassem, Moustapha
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.05.2019; Elsevier
• Subjects: adipogenesis; adipose-derived stem cells; bone marrow skeletal stem cells; differentiation potential; insulin signaling; obesity; skeletal fragility; skeletal fragility; adipose-derived stem cells; adipogenesis; insulin signaling; differentiation potential; bone marrow skeletal stem cells; obesity
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.04.066

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. [Display omitted] •Obesity accelerates differentiation potential of bone marrow stromal stem cells (BM-MSCs)•Obesity shifts molecular phenotype of BM-MSCs toward committed adipocytic progenitors•Obesity increases insulin signaling in BM-MSCs in contrast to adipose tissue-derived MSCs•IR+ and LEPR+ cells in obese BM-MSCs are associated with accelerated senescence 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.