RT Journal Article SR Electronic T1 Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance JF Diabetes JO Diabetes FD American Diabetes Association SP 1730 OP 1746 DO 10.2337/db18-0927 VO 68 IS 9 A1 Zhou, Meiyi A1 Shao, Jing A1 Wu, Cheng-Yang A1 Shu, Le A1 Dong, Weibing A1 Liu, Yunxia A1 Chen, Mengping A1 Wynn, R. Max A1 Wang, Jiqiu A1 Wang, Ji A1 Gui, Wen-Jun A1 Qi, Xiangbing A1 Lusis, Aldons J. A1 Li, Zhaoping A1 Wang, Weiqing A1 Ning, Guang A1 Yang, Xia A1 Chuang, David T. A1 Wang, Yibin A1 Sun, Haipeng YR 2019 UL http://diabetes.diabetesjournals.org/content/68/9/1730.abstract AB Recent studies implicate a strong association between elevated plasma branched-chain amino acids (BCAAs) and insulin resistance (IR). However, a causal relationship and whether interrupted BCAA homeostasis can serve as a therapeutic target for diabetes remain to be established experimentally. In this study, unbiased integrative pathway analyses identified a unique genetic link between obesity-associated IR and BCAA catabolic gene expression at the pathway level in human and mouse populations. In genetically obese (ob/ob) mice, rate-limiting branched-chain α-keto acid (BCKA) dehydrogenase deficiency (i.e., BCAA and BCKA accumulation), a metabolic feature, accompanied the systemic suppression of BCAA catabolic genes. Restoring BCAA catabolic flux with a pharmacological inhibitor of BCKA dehydrogenase kinase (BCKDK) ( a suppressor of BCKA dehydrogenase) reduced the abundance of BCAA and BCKA and markedly attenuated IR in ob/ob mice. Similar outcomes were achieved by reducing protein (and thus BCAA) intake, whereas increasing BCAA intake did the opposite; this corroborates the pathogenic roles of BCAAs and BCKAs in IR in ob/ob mice. Like BCAAs, BCKAs also suppressed insulin signaling via activation of mammalian target of rapamycin complex 1. Finally, the small-molecule BCKDK inhibitor significantly attenuated IR in high-fat diet–induced obese mice. Collectively, these data demonstrate a pivotal causal role of a BCAA catabolic defect and elevated abundance of BCAAs and BCKAs in obesity-associated IR and provide proof-of-concept evidence for the therapeutic validity of manipulating BCAA metabolism for treating diabetes.