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

Michaela Tencerova; Morten Frost; Florence Figeac; Tina Kamilla Nielsen; Dalia Ali; Jens Jacob Lindegaard Lauterlein; Thomas Levin Andersen; Anders Kristian Haakonsson; Alexander Rauch; Jonna Skov Madsen; Charlotte Ejersted; Kurt Højlund; Moustapha Kassem

doi:10.1016/j.celrep.2019.04.066

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

Michaela Tencerova^*, Morten Frost, Florence Figeac, Tina Kamilla Nielsen, Dalia Ali, Jens Jacob Lindegaard Lauterlein, Thomas Levin Andersen, Anders Kristian Haakonsson, Alexander Rauch, Jonna Skov Madsen, Charlotte Ejersted, Kurt Højlund, Moustapha Kassem

^*Corresponding author for this work

Morphogenesis and Differentiation Program

28 Citations (Scopus)

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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. 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.

Original language	English
Journal	Cell Reports
Volume	27
Issue number	7
Pages (from-to)	2050-2062.e6
ISSN	2211-1247
DOIs	https://doi.org/10.1016/j.celrep.2019.04.066
Publication status	Published - 2019

Keywords

adipogenesis
adipose-derived stem cells
bone marrow skeletal stem cells
differentiation potential
insulin signaling
obesity
skeletal fragility

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Obesity-Associated Hypermetabolism and Accelerated Senescence of Bone Marrow Stromal Stem Cells Suggest a Potential Mechanism for Bone FragilityFinal published version, 2.27 MBLicence: CC BY

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Tencerova, M., Frost, M., Figeac, F., Nielsen, T. K., Ali, D., Lauterlein, J. J. L., Andersen, T. L., Haakonsson, A. K., Rauch, A., Madsen, J. S., Ejersted, C., Højlund, K., & Kassem, M. (2019). Obesity-Associated Hypermetabolism and Accelerated Senescence of Bone Marrow Stromal Stem Cells Suggest a Potential Mechanism for Bone Fragility. Cell Reports, 27(7), 2050-2062.e6. https://doi.org/10.1016/j.celrep.2019.04.066

Tencerova, M, Frost, M, Figeac, F, Nielsen, TK, Ali, D, Lauterlein, JJL, Andersen, TL, Haakonsson, AK, Rauch, A, Madsen, JS, Ejersted, C, Højlund, K & Kassem, M 2019, 'Obesity-Associated Hypermetabolism and Accelerated Senescence of Bone Marrow Stromal Stem Cells Suggest a Potential Mechanism for Bone Fragility', Cell Reports, vol. 27, no. 7, pp. 2050-2062.e6. https://doi.org/10.1016/j.celrep.2019.04.066

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

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. 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 = "adipogenesis, adipose-derived stem cells, bone marrow skeletal stem cells, differentiation potential, insulin signaling, obesity, skeletal fragility",

author = "Michaela Tencerova and Morten Frost and Florence Figeac and Nielsen, {Tina Kamilla} and Dalia Ali and Lauterlein, {Jens Jacob Lindegaard} and Andersen, {Thomas Levin} and Haakonsson, {Anders Kristian} and Alexander Rauch and Madsen, {Jonna Skov} and Charlotte Ejersted and Kurt H{\o}jlund and Moustapha Kassem",

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T1 - Obesity-Associated Hypermetabolism and Accelerated Senescence of Bone Marrow Stromal Stem Cells Suggest a Potential Mechanism for Bone Fragility

AU - Tencerova, Michaela

AU - Frost, Morten

AU - Figeac, Florence

AU - Nielsen, Tina Kamilla

AU - Ali, Dalia

AU - Lauterlein, Jens Jacob Lindegaard

AU - Andersen, Thomas Levin

AU - Haakonsson, Anders Kristian

AU - Rauch, Alexander

AU - Madsen, Jonna Skov

AU - Ejersted, Charlotte

AU - Højlund, Kurt

AU - Kassem, Moustapha

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - adipogenesis

KW - adipose-derived stem cells

KW - bone marrow skeletal stem cells

KW - differentiation potential

KW - insulin signaling

KW - obesity

KW - skeletal fragility

U2 - 10.1016/j.celrep.2019.04.066

DO - 10.1016/j.celrep.2019.04.066

M3 - Journal article

C2 - 31091445

AN - SCOPUS:85065169436

SN - 2211-1247

VL - 27

SP - 2050-2062.e6

JO - Cell Reports

JF - Cell Reports

IS - 7

ER -

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

Abstract

Keywords

UN SDGs

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