Uncovering mechanisms of thiazolidinediones on osteogenesis and adipogenesis using spatial fluxomics
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00617583" target="_blank" >RIV/61388963:_____/25:00617583 - isvavai.cz</a>
Alternative codes found
RIV/67985823:_____/25:00617583 RIV/00216208:11310/25:10498771
Result on the web
<a href="https://doi.org/10.1016/j.metabol.2025.156157" target="_blank" >https://doi.org/10.1016/j.metabol.2025.156157</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.metabol.2025.156157" target="_blank" >10.1016/j.metabol.2025.156157</a>
Alternative languages
Result language
angličtina
Original language name
Uncovering mechanisms of thiazolidinediones on osteogenesis and adipogenesis using spatial fluxomics
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10401 - Organic chemistry
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Metabolism-Clinical and Experimental
ISSN
0026-0495
e-ISSN
1532-8600
Volume of the periodical
166
Issue of the periodical within the volume
May
Country of publishing house
US - UNITED STATES
Number of pages
12
Pages from-to
156157
UT code for WoS article
001428185600001
EID of the result in the Scopus database
2-s2.0-85217663191