Donor-specific response of visceral adipocytes differentiated from human adipose-derived mesenchymal stem cells to branched-chain alpha-keto acid (BCKA) dehydrogenase activation.

AIMS: The causal role of branched-chain amino acids (BCAAs) and their transamination derivatives (branched-chain α-ketoacids, BCKAs) was observed in the progression of obesity and its metabolic complications. In the study, we aimed to stimulate BCAA catabolic flux with an inhibitor of BCKA dehydrogenase kinase (i.e., BT2) to explore metabolic consequences using visceral ADMSCs, obtained from non-obese men and men with obesity, and differentiated to adipocytes.

MATERIALS AND

METHODS

ADMSCs metabolism was assessed using real-time PCR, Western Blot, Ultra-High Performance Liquid Chromatography, Gas-Liquid Chromatography, Seahorse analysis, liquid scintillation counting, flow cytometry, immunofluorescence and spectrophotometric assays.

RESULTS

We report that obesity was associated with the redistribution of fatty acid transporters among a higher number of adipocytes (higher number of CD36/SR-B2 and FATP4 positive cells), but at the same time lowered surface abundance of transporters per cell (CD36/SR-B2, FATP1, FATP4, FABPpm). Despite that, the metabolic consequences of BT2 administration were strictly associated with the donor-specific inherent cellular properties, what enabled a differentiation of two adipocyte subpopulations with low and high metabolic activity. BT2 effects were more profound in the latter group, wherein pro-lipolytic and β-oxidation-related markers were upregulated, including higher ATP production, glycerol release and acid-soluble metabolites accumulation, reduced fatty acid synthase expression, decreased free fatty acids and triacylglycerols concentrations.

CONCLUSIONS

Our data highlight the substantial contribution of BCAA catabolism in adipocyte lipogenesis, and effective utilization of energy substrates. The more efficient the regulation of fat storage in the adipocytes, the less would be the lipotoxic effects in non-adipose tissues.