Novel Functions Of Branched-chain Amino Acid In Insulin Resistance And Myocardial Protection

Branched-chain Amino Acid(BCAA),including leucine,isoleucine and valine,are essential amino acids with various functions in cells.Recent studies have revealed a significant association between elevated plasma BCAA in metabolic and cardiovascular diseases.However,the causal relationship,underlying mechanisms,and therapeutic potential remain to be established.Our study found that BCAA and their metabolites exert different impacts on insulin sensitivity in obese and lean mice.In obese mice,we found BCAA catabolic deficiency led to elevated levels of BCAA and particularly BCKA(branched-chain ?-keto acid).A BCAA tolerance test was developed to accurately detect this BCAA catabolic defect.Lowering protein intake restored BCAA/BCKA levels and attenuated insulin resistance(IR),whereas increasing BCAA uptake did the opposite,supporting a causal role of BCAA catabolic deficiency in the pathogenesis of IR.Elevated BCAA/BCKA suppressed the expression of an insulin-sensitizing adipokine Sfrp5.Overexpression of Sfrp5 attenuated BCAA/BCKA-induced IR,indicating loss of Sfrp5 expression was at least in part responsible for the impact of BCAA catabolic defect on IR in obese mice.In lean mice,on the other hand,increased BCAA/BCKA led to lower adiposity and free fatty acid concentrations in plasma and skeletal muscle,accompanied with enhanced insulin sensitivity and glucose tolerance.Therefore,BCAA/BCKA may affect insulin sensitivity in different directions in lean and obese mice.In addition to insulin sensitivity,BCKA inhibited mitochondrial respiration.Similar to other chemical inhibitors of mitochondrial respiratory complexes,BCKA significantly attenuated ischemia-reperfusion(I/R)injury in isolated mouse hearts.Mechanistically,BCKA attenuated oxidative stress induced cell death by inhibiting necrosis.BCKA protected mitochondria and energy production from oxidative injury.Finally,administration of BCKA during reperfusion was sufficient to significantly attenuate cardiac I/R injury.Together,our studies uncovered novel roles of BCAA/BCKA in metabolic and cardiovascular diseases,providing new strategy and potential targets for the prevention and treatment of these disorders.