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

Cell Rep. 2019 May 14;27(7):2050-2062.e6. doi: 10.1016/j.celrep.2019.04.066.

Abstract

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.

Keywords: adipogenesis; adipose-derived stem cells; bone marrow skeletal stem cells; differentiation potential; insulin signaling; obesity; skeletal fragility.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Marrow Cells / metabolism*
  • Bone Marrow Cells / pathology
  • Bone and Bones / metabolism*
  • Bone and Bones / pathology
  • Cell Differentiation*
  • Cellular Senescence*
  • Humans
  • Male
  • Mesenchymal Stem Cells / metabolism*
  • Mesenchymal Stem Cells / pathology
  • Obesity / metabolism*
  • Obesity / pathology