Metabolic Heterogeneity in Adipocytes Treated with BT2 Kinase Inhibitor

Adipose-derived mesenchymal stromal cells (ADMSCs) display heterogeneous metabolic responses that may underlie variable adipocyte phenotype and function. This study 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. Understanding these metabolic variations is relevant for laboratory research into tissue-specific responses to metabolic modulators.

The researchers classified the cells 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. These findings highlight the importance of considering individual variability when evaluating metabolic interventions at the cellular level. The study provides a framework for understanding how specific inhibitors may influence distinct subpopulations of adipocytes.

This research underscores the need for careful characterization of cell populations before applying metabolic modulators in experimental settings. While the results are promising, further validation is required to determine clinical relevance and potential therapeutic applications.