机构：[1]Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China[2]Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX[3]Department of Integrative Biology and Physiology, University of California at Los Angeles, Los Angeles, CA[4]Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China[5]Chemistry Center, National Institute of Biological Science, Beijing, China[6]Departments of Medicine, Microbiology, and Human Genetics, University of California at Los Angeles, Los Angeles, CA[7]Department of Clinical Nutrition, University of California at Los Angeles, Los Angeles, CA[8]Departments of Anesthesiology, Medicine, and Physiology, University of California at Los Angeles, Los Angeles, CA
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 alpha-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.
基金：
This work was supported by the Ministry of Science and Technology
of China (grant nos. 2012BAI02B05 and 2013YQ030923), the National International
Science Cooperation Foundation (grant no. 2015DFA30560), the National
Natural Science Foundation of China (grant nos. NSFC81570717 and 81522011),
the National Institutes of Health (grant nos. HL108186, HL103205, HL098954, and
DK62306), the National Heart, Lung, and Blood Institute (grant no. HL080111), the
Laubisch Fund (to the University of California Los Angeles), the Welch Foundation
(grant no. I-1286), and the Science and Technology Commission of Shanghai
Municipality (grant nos. 13ZR1423300 and 16JC1404400). L.S. is supported by
a China Scholarship Council scholarship, a UCLA Eureka and Hyde scholarship,
and a Burroughs Wellcome Fund fellowship. X.Y. is supported by the National
Institutes of Health/National Institute of Diabetes and Digestive and Kidney
Diseases (grant no. R01DK104363), the American Heart Association (grant no.
13SDG17290032), an American Heart Association Cardiovascular Genome-
Phenome Study Pathway Grant, and a Leducq Foundation Transatlantic Networks
of Excellence Grant.
第一作者机构：[1]Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
共同第一作者：
通讯作者：
通讯机构：[1]Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China[8]Departments of Anesthesiology, Medicine, and Physiology, University of California at Los Angeles, Los Angeles, CA
医学