High Glucose Level Impairs Human Mature Bone Marrow Adipocyte Function Through Increased ROS Production

Abstract

Bone marrow adipocytes (BMAds) accumulate in aging, menopause, and metabolic diseases such as Type 2 diabetes. These osteoporotic conditions are associated with oxidative stress and hyperglycemia which are both considered as critical factors underlying bone fragility. Glucose excess and reactive oxygen species (ROS) are known to favor adipogenesis over osteoblastogenesis. In this study, we investigated whether high glucose exposure could determine dysfunction of mature BMAds, specifically through ROS production. The effects of low (LG, 5 mM) or high glucose (HG, 25 mM) concentrations were examined using human bone mesenchymal stromal cells (hBMSCs) in the time course of differentiation, and, up to 21 days once adipocytes were mature. HG did not alter the adipocyte differentiation process of hBMSCs. Yet, after 21 days under HG exposure, PPARG, CEBPA, and adiponectin mRNA expressions were decreased. These alterations were also observed following adipogenic inducer withdrawal as well as in adipocytes fully differentiated in LG then cultured in HG for the last 11 days. Without inducers, HG condition also led to decreased leptin mRNA level. Importantly, intracellular and extracellular ROS concentrations measured using Amplex Red were significantly raised by 50% under HG exposure. This rise was observed once adipocytes ended differentiation and was reproduced within the different cell culture settings without any cytotoxicity. Among genes involved in ROS metabolism, the mRNA level of the H2O2 generating enzyme NOX4 was found upregulated in the presence of HG. Following cell separation, mature BMAds were shown to overproduce ROS and to display the gene alterations in contrast to non-lipid-laden cells. Finally, a non-lethal treatment with a pro-oxidant agent under LG condition reduces the mRNA levels of PPARG, adiponectin, and leptin as the HG condition does in the absence of inducers, and amplifies the effect of glucose excess on gene expression. HG concentration drives mature BMAds toward altered expression of the main adipokines and transcriptional factors. These perturbations are associated with a rise in ROS generation likely mediated through enhanced expression of NOX4. Mature BMAds are thus responsive to changes in glucose and ROS concentrations, which is relevant regarding with their phenotype and function in age- or metabolic disease-related osteoporosis.

Role of Hyperglycemia in the Senescence of Mesenchymal Stem Cells

“…This high glucose-induced biological reaction is associated with ROS-mediated Akt attenuation (Cheng et al, 2016). Consistent with previous studies, Rharass et al showed that intracellular and extracellular ROS concentrations were significantly increased by 50% under high glucose exposure, paralleled by increased mRNA levels of the H 2 O 2 generating enzyme NADPH oxidase 4 (Rharass and Lucas, 2019). All of the studies reviewed here support the notion that hyperglycemia drive mitochondrial dysfunction through the ROS pathway which is fundamental to the senescence of MSCs.…”

“…However, GDM-UCMSCs demonstrated a significantly lower adipogenic potential (Kim et al, 2015;Moseley et al, 2018). Furthermore, another study found that BMSCs showed decreased adipogenic differentiation capability under high glucose conditions and that the mRNA expression of peroxisome proliferator activated receptor gamma, CCAAT/enhancerbinding protein alpha, leptin, and adiponectin in BMSCs decreased (Rharass and Lucas, 2019). Interestingly, when cultured in an appropriate induction medium, both AMSCs from diabetic donors (dAMSCs) and from non-diabetic donors (nAMSCs) exhibited potential for trans-differentiation into neuron-like cells via a reactive oxygen species (ROS)-mediated mechanism (Cheng et al, 2016).…”

[Retracted] Natural Antioxidants Improve the Vulnerability of Cardiomyocytes and Vascular Endothelial Cells under Stress Conditions: A Focus on Mitochondrial Quality Control

“…Under normal physiological conditions, the surrounding tissues respond to insulin by increasing the expression of glucose transporters on the plasma membrane. However, consistent high glucose levels and consequent long-term high insulin levels will lead to insulin resistance [ 134 ]. High levels of insulin interfere with NOX4 signal transduction and enhance ROS production [ 135 ].…”

Loganin Attenuates High Glucose-Induced Schwann Cells Pyroptosis by Inhibiting ROS Generation and NLRP3 Inflammasome Activation

“…To simulate an uncontrolled diabetic state, we designed to culture the cells in 25-mM glucose and investigated the effect of high glucose on the viability of RSC96 cells. The 5.6-mM glucose medium is close to physiological levels [ 34 , 35 , 36 , 37 ]. Cell viability was measured by CCK 8 (cell counting kit 8) assay.…”