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• W2948852497 abstract "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." @default.
• W2948852497 created "2019-06-14" @default.
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• W2948852497 date "2019-08-14" @default.
• W2948852497 modified "2023-10-16" @default.
• W2948852497 title "Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance" @default.
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• W2948852497 doi "https://doi.org/10.2337/db18-0927" @default.
• W2948852497 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6702639" @default.
• W2948852497 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/31167878" @default.
• W2948852497 hasPublicationYear "2019" @default.
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