Cardiac Branched-Chain Amino Acid Oxidation is Reduced During Insulin Resistance in the Heart.

Recent studies have proposed that elevated branched-chain amino acids (BCAAs) may induce insulin resistance (IR) in muscle secondary to increased BCAA oxidation inhibiting glucose oxidation (GO) and fatty acid oxidation (FAO). However, BCAA oxidation rates have not been assessed in muscle IR and cardiac FAO rates are elevated in obesity-associated IR. We examined cardiac BCAA oxidation in mice fed a high fat diet (HFD) to induce IR to better understand the role of cardiac BCAA oxidation in cardiac IR. BCAA oxidation, GO, FAO, and glycolysis were measured in isolated working hearts from mice fed a low fat diet (LFD) or HFD for 10 wk. Insulin stimulation of cardiac GO and inhibition of FAO was blunted in HFD mice, resulting in a marked increase in FAO contribution to ATP production compared to LFD mice hearts (71.2% vs 37.1%, respectively). Surprisingly, cardiac BCAA oxidation rate was reduced in HFD compared to LFD mice (33.5±3.4 vs 56.7±7.1 nmol.min-1 .g dry wt-1 , respectively, p<0.05, n=9/group). In addition, BCAA oxidation contributed approximately 1% of the heart's ATP production and as a result alterations in BCAA oxidation could not significantly impact either GO or FAO rates. However, the decrease in BCAA oxidation was accompanied by increased BCAA concentration, and impaired insulin signaling. These results suggest that cardiac IR is not due to an increase in BCAA oxidation and subsequent inhibition of GO and FAO. Rather, we propose that an inhibition of BCAA oxidation rate contributes to IR by leading to increased BCAA concentration, which negatively impacts insulin signaling.