Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Zhou, M; Shao, J; Wu, C-Y; Shu, L; Dong, W; Liu, Y; Chen, M; Wynn, RM; Wang, J; Wang, J; Gui, W-J; Qi, X; Lusis, AJ; Li, Z; Wang, W; Ning, G; Yang, X; Chuang, DT; Wang, Y; Sun, H

Published Date

  • September 2019

Published In

Volume / Issue

  • 68 / 9

Start / End Page

  • 1730 - 1746

PubMed ID

  • 31167878

Pubmed Central ID

  • PMC6702639

Electronic International Standard Serial Number (EISSN)

  • 1939-327X

Digital Object Identifier (DOI)

  • 10.2337/db18-0927

Language

  • eng

Conference Location

  • United States