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.