Novel Roles Of Branched-chain Amino Acids And Their Catabolic Intermediates In Glucose And Lipid Metabolic Regulation

Lipid plays a central role in maintaining metabolic homeostasis.Recent studies demonstrate elevated plasma branched-chain amino acids(BCAAs)in human with obesity and insulin resistance.However,the crosstalk and causality between BCAA,lipid metabolism,and insulin resistance remain unclear.Here we revealed that BCAA catabolic defect reduced adipose tissue mass in PP2 Cm null mice and impaired adipogenesis cell-autonomously.Meanwhile,adipose-specific BCKDK knockout mice,with enhanced BCAA catabolism,showed increases in fat mass and improved adipogenesis ex vivo.During 3T3-L1 pre-adipocytes differentiation,BCAA catabolism was dramatically induced and required for sustaining the adipogenic transcriptional program but not lipogenesis.A leucine catabolic intermediate played a critical role in supporting the expression of two master regulators of adipogenic transcriptional program,PPARγ and C/EBPα.The leucine catabolite activated the mechanistic Target of Rapamycin Complex 1(mTORC1)to sustain S-adenosylmethionine decarboxylases 1(AMD1)expression and thus methionine metabolism to spermidine,one polyamine indispensable for PPARγ and C/EBPα expression.Furthermore,the leucine catabolic intermediate promoted adiposity in wild type mice.Thus,a catabolite-driven regulatory network involving leucine,methionine,and polyamine underlies adipogenesis,mediated a previously unrecognized crosstalk between amino acids and lipid metabolism.In addition to the crosstalk between BCAA and lipid metabooism,we found a pivotal causal role of BCAA catabolic defect and elevated BCAA/BCKA in obesity-associated IR.In obese(ob/ob)mice,the systemic suppression of BCAA catabolic genes was accompanied with a metabolic feature of rate-limiting branched-chain alpha-keto acid dehydrogenase(BCKDH)deficiency,i.e.,BCAA and branched-chain α-keto acid(BCKA)accumulation.Restoring BCAA catabolic flux with a pharmacological inhibitor of BCKD kinase(BCKDK,a suppressor of BCKDH)reduced BCAA/BCKA abundances and markedly attenuated IR in ob/ob mice.Similar outcomes were achieved by lowering protein(thus BCAA)intake,while increasing BCAA intake did the opposite,corroborating the pathogenic roles of BCAA/BCKA in IR.Like BCAA,BCKA also suppressed insulin signaling via mTORC1 activation.Together,these results suggest that BCAA catabolism played an essential regulatory role in adipogenesis,obesity and obesity-associated insulin resistance.