Obesity‐related Elevations in Plasma Leucine are Associated with Defective Branched Chain Amino Acid (BCAA) Metabolism

Obesity is associated with elevated plasma concentrations of BCAAs. The mechanisms underlying these rises are not clear but are of recent interest given leucine’s role as a regulator of satiety, leptin, mTOR and PKC signaling. Obese ob/ob mice had elevated plasma BCAA concentrations in the fed state and after overnight food deprivation. Defective BCAA metabolism could underlie the changes, therefore we examined the first two steps in leucine metabolism: mitochondrial BCAA transaminase (BCATm) and branched chain keto acid dehydrogenase (BCKD). No obesity‐related change in expression of these enzymes was found in muscle from ob/ob mice. However, in adipose tissues, BCATm and BCKD protein expression was lower in obese compared to lean controls. BCKD kinase, which inhibits BCKD, was elevated obese fat. In morbidly obese humans BCAAs, adipose tissue BCATm and BCKD normalized after gastric bypass surgery. In liver, which does not express BCATm, no change in BCKD subunit protein concentration was observed, however pS293 phosphorylation of the E1‐α subunit of BCKD, which negatively regulates BCKD activity, was increased in ob/ob livers, co‐incident with increased expression of BCKD kinase. The emerging results appear to support the notion that reversible tissue specific alterations in BCAA metabolism might contribute to the rise in BCAAs in obesity. (NIH DK053843 , DK62880, DK34738).