Adipose-Derived Mesenchymal Stromal Cells Display Heterogeneous Metabolic Responses

Adipose-derived mesenchymal stromal cells (ADMSCs) display heterogeneous metabolic responses that may underlie variable adipocyte phenotype and function. This study examined how BT2, a branched-chain α-ketoacid dehydrogenase (BCKDH) kinase inhibitor, influences 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 mechanisms is relevant for metabolic research contexts where individual variability in cellular response to pharmacological agents must be accounted for.

The authors classified adipocytes as responders or 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. This paper highlights the importance of characterizing individual cellular responses when evaluating metabolic interventions. The findings suggest that variability in sphingolipid metabolism and signaling pathways may contribute to differential outcomes in adipocyte function.

It is important to note that this research was conducted using mature adipocytes differentiated from visceral ADMSCs obtained from non-obese and obese men. The study does not provide clinical recommendations or medical advice for human application. These results should be interpreted within the context of laboratory-based metabolic research, where cellular heterogeneity remains a critical factor in interpreting pharmacological effects.