OBJECTIVE: The use of thiazolidinediones (TZDs) as insulin sensitizers has been shown to have side effects including increased accumulation of bone marrow adipocytes (BMAds) associated with a higher fracture risk and bone loss. A novel TZD analog MSDC-0602K with low affinity to PPARγ has been developed to reduce adverse effects of TZD therapy. However, the effect of MSDC-0602K on bone phenotype and bone marrow mesenchymal stem cells (BM-MSCs) in relation to obesity has not been intensively studied yet. METHODS: Here, we investigated whether 8-week treatment with MSDC-0602K has a less detrimental effect on bone loss and BM-MSC properties in obese mice in comparison to first generation of TZDs, pioglitazone. Bone parameters (bone microstructure, bone marrow adiposity, bone strength) were examined by μCT and 3-point bending test. Primary BM-MSCs were isolated and measured for osteoblast and adipocyte differentiation. Cellular senescence, bioenergetic profiling, nutrient consumption and insulin signaling were also determined. RESULTS: The findings demonstrate that MSDC-0602K improved bone parameters along with increased proportion of smaller BMAds in tibia of obese mice when compared to pioglitazone. Further, primary BM-MSCs isolated from treated mice and human BM-MSCs revealed decreased adipocyte and higher osteoblast differentiation accompanied with less inflammatory and senescent phenotype induced by MSDC-0602K vs. pioglitazone. These changes were further reflected by increased glycolytic activity differently affecting glutamine and glucose cellular metabolism in MSDC-0602K-treated cells compared to pioglitazone, associated with higher osteogenesis. CONCLUSION: Our study provides novel insights into the action of MSDC-0602K in obese mice, characterized by the absence of detrimental effects on bone quality and BM-MSC metabolism when compared to classical TZDs and thus suggesting a potential therapeutical use of MSDC-0602K in both metabolic and bone diseases.

Biomechanics lab Institute of Mechanics Materials and Civil Engineering UCLouvain Louvain la Neuve Belgium; Department of Materials Engineering KU Leuven Belgium; Prometheus Division of Skeletal Tissue Engineering Katholieke Universiteit Leuven 3000 Leuven Belgium; Pole of Morphology Institute for Experimental and Clinical Research UCLouvain Brussels Belgium

Biomechanics lab Institute of Mechanics Materials and Civil Engineering UCLouvain Louvain la Neuve Belgium; Pole of Morphology Institute for Experimental and Clinical Research UCLouvain Brussels Belgium; Department of Chemistry Molecular Design and Synthesis KU Leuven Leuven Belgium

Czech Centre for Phenogenomics and Laboratory of Transgenic Models of Diseases Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Department of Mechanical Engineering KU Leuven Leuven Belgium

FIBEr KU Leuven Leuven Belgium

Laboratory of Adipose Tissue Biology Institute of Physiology of the Czech Academy of Sciences Prague 142 20 Czech Republic

Laboratory of Bioenergetics Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Molecular Physiology of Bone Institute of Physiology of the Czech Academy of Sciences Prague 142 20 Czech Republic

Laboratory of Molecular Physiology of Bone Institute of Physiology of the Czech Academy of Sciences Prague 142 20 Czech Republic; Faculty of Science Charles University Prague Czech Republic

Laboratory of Translational Metabolism Institute of Physiology of the Czech Academy of Sciences Prague 142 20 Czech Republic

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