Paper of the Month - June 2025
selected by the BMAS Scientific Board

Uncovering mechanisms of thiazolidinediones on osteogenesis and adipogenesis using spatial fluxomics

Kristyna Brejchova1Michal Rahm2Andrea Benova3Veronika Domanska1Paul Reyes-Gutierez2Martina Dzubanova4Radka Trubacova1Michaela Vondrackova1Tomas Cajka5Michaela Tencerova3Milan Vrabel2Ondrej Kuda6

1 Laboratory of Metabolism of Bioactive Lipids, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14200 Prague, Czechia.

2 Chemistry of Bioconjugates, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 166 10 Prague, Czechia.

3 Laboratory of Molecular Physiology of Bone, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14200 Prague, Czechia.

4 Laboratory of Molecular Physiology of Bone, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14200 Prague, Czechia; Faculty of Science, Charles University, Albertov 6, 128 00 Prague, Czech Republic.

5 Laboratory of Translational Metabolism, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14200 Prague, Czechia.

6 Laboratory of Metabolism of Bioactive Lipids, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14200 Prague, Czechia. 

Correspondence: ondrej.kuda@fgu.cas.cz.

 

Metabolism 2025 May: 166:156157

PMID: 39947516 | DOI: 10.1016/j.metabol.2025.156157

 

Abstract

 

Objective: Insulin-sensitizing drugs, despite their broad use against type 2 diabetes, can adversely affect bone health, and the mechanisms underlying these side effects remain largely unclear. Here, we investigated the different metabolic effects of a series of thiazolidinediones, including rosiglitazone, pioglitazone, and the second-generation compound MSDC-0602K, on human mesenchymal stem cells (MSCs).

Methods: We developed 13C subcellular metabolomic tracer analysis measuring separate mitochondrial and cytosolic metabolite pools, lipidomic network-based isotopologue models, and bioorthogonal click chemistry, to demonstrate that MSDC-0602K differentially affected bone marrow-derived MSCs (BM-MSCs) and adipose tissue-derived MSCs (AT-MSCs). In BM-MSCs, MSDC-0602K promoted osteoblastic differentiation and suppressed adipogenesis. This effect was clearly distinct from that of the earlier drugs and that on AT-MSCs.

Results: Fluxomic data reveal unexpected differences between this drug’s effect on MSCs and provide mechanistic insight into the pharmacologic inhibition of mitochondrial pyruvate carrier 1 (MPC). Our study demonstrates that MSDC-0602K retains the capacity to inhibit MPC, akin to rosiglitazone but unlike pioglitazone, enabling the utilization of alternative metabolic pathways. Notably, MSDC-0602K exhibits a limited lipogenic potential compared to both rosiglitazone and pioglitazone, each of which employs a distinct lipogenic strategy.

Conclusions: These findings indicate that the new-generation drugs do not compromise bone structure, offering a safer alternative for treating insulin resistance. Moreover, these results highlight the ability of cell compartment-specific metabolite labeling by click reactions and tracer metabolomics analysis of complex lipids to discover molecular mechanisms within the intersection of carbohydrate and lipid metabolism.

 

Graphical Abstract