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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.