Unknown

Dataset Information

0

Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance.


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.

SUBMITTER: Zhou M 

PROVIDER: S-EPMC6702639 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC4254305 | biostudies-literature
| S-EPMC6776356 | biostudies-literature
| S-EPMC5499371 | biostudies-literature
| S-EPMC4023466 | biostudies-literature
| S-EPMC3063199 | biostudies-literature
| S-EPMC6354586 | biostudies-literature
| S-EPMC6715529 | biostudies-literature
| S-EPMC3989800 | biostudies-literature
| S-EPMC4392118 | biostudies-literature
| S-EPMC2844835 | biostudies-other