- Article
- Open access
- Published:
- Bartłomiej Łukaszuk1,
- Marcin Baranowski1,
- Adrian Chabowski1 &
- …
- Agnieszka Mikłosz1
Scientific Reports (2026) Cite this article
We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.
Abstract
Adipose-derived mesenchymal stromal cells (ADMSCs) display heterogeneous metabolic responses that may underlie variable adipocyte phenotype and function. Here, we investigated the effects of BT2, a branched-chain α-ketoacid dehydrogenase (BCKDH) kinase inhibitor, on sphingolipid metabolism, phosphorylation of proteins involved in insulin action, and adipokine secretion using mature adipocytes differentiated from visceral ADMSCs obtained from non-obese and obese men. The cells were classified as responders and non-responders based on the branched-chain keto acids (BCKA)/branched-chain amino acids (BCAA) ratio after BT2 exposure. Responders exhibited a reduced BCKA/BCAA ratio indicative of effective BCKDH activation and mitochondrial BCKA flux. Further experiments showed that BT2 treatment increased intracellular ceramide, sphingosine, and sphingomyelin content, concomitantly with decreased leptin, adiponectin, and visfatin secretion in the responders. Moreover, the responder cells had a higher phosphorylation ratio of Akt (Ser473) and GSK3, while mTORC1 (Ser2481) expression was reduced due to BT2. In contrast, the non-responder adipocytes exhibited higher BCKA/BCAA ratios associated with increased intracellular sphingosine and sphingosine-1-phosphate levels and enhanced IRS1 and mTORC1 phosphorylation following BT2 treatment. Additionally, reduced adipsin content in the culture medium and elevated secretion of leptin, visfatin, and PAI-1 were noticed. Altogether, our data indicate that adipocytes from different individuals exhibit intrinsic heterogeneity in their metabolic adaptation to enhanced BCAA catabolism.
Subjects
Funding
This work was supported by the National Science Centre (grant no. 2020/04/X/NZ3/00406) and the Medical University of Bialystok (grant numbers B.SUB.24.399 and B.SUB.25.395).
Ethics declarations
Competing interests
The authors declare no competing interests.
Ethics approval
The study was approved by the Ethics Committee of the Medical University of Bialystok (permission number: R-I-002/187/2017, date of approval: 25.05.2017; APK.002.108.2021, date of approval: 25.02.2021). All procedures were designed, conducted, and reported in compliance with the Declaration of Helsinki 1975, according to the guidelines for Good Clinical Practice. All subjects gave their informed consent to participate in the study.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Reprints and permissions
About this article
Cite this article
Supruniuk, E., Łukaszuk, B., Baranowski, M. et al. Branched-chain α-ketoacid dehydrogenase activation reveals divergent sphingolipid and adipokine responses in adipocytes differentiated from visceral adipose-derived mesenchymal stromal cells (ADMSCs). Sci Rep (2026). https://doi.org/10.1038/s41598-026-66661-4
Download citation
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41598-026-66661-4