Journal
CELL REPORTS
Volume 27, Issue 7, Pages 2050-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.04.066
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Funding
- Danish Diabetes Academy
- Novo Nordisk Foundation [NNF18OC0034186]
- Lundbeck Foundation [R266-2017-4250]
- Danish Independent Research Council [DFF-1333-00283]
- Region Syddanmarks
- Odense University Hospital [R29-A1374]
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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.
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