Format

Send to

Choose Destination
Diabetes. 2019 Jun 5. pii: db180927. doi: 10.2337/db18-0927. [Epub ahead of print]

Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance.

Author information

1
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
2
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9038, USA.
3
Department of Integrative Biology and Physiology, University of California at Los Angeles, Los Angeles, CA 90095, USA.
4
Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
5
Chemistry Center, National Institute of Biological Science, Beijing 102206, China.
6
Department of Medicine, Microbiology and Human Genetics, University of California at Los Angeles, Los Angeles, CA 90095, USA.
7
Department of Clinical Nutrition, University of California at Los Angeles, Los Angeles, CA 90095, USA.
8
Departments of Anesthesiology, Medicine and Physiology, University of California, Los Angeles, CA 90095, USA.
9
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China sun.haipeng@yahoo.com.

Abstract

Recent studies implicate a strong association between elevated plasma branched-chain amino acids (BCAAs) and insulin resistance (IR). However, the causal relationship and whether the interrupted BCAA homeostasis can serve as a therapeutic target for diabetes remain to be established experimentally. In the present study, unbiased integrative pathway analyses identified a unique genetic link between obesity-associated IR and BCAA catabolic gene expression at pathway-level in human and mouse populations. In genetically obese ( ob/ob) mice, the systemic suppression of BCAA catabolic genes was accompanied with a metabolic feature of rate-limiting branched-chain alpha-keto acid dehydrogenase (BCKD) deficiency, i.e., BCAA and branched-chain α-keto acid (BCKA) accumulation. Restoring BCAA catabolic flux with a pharmacological inhibitor of BCKD kinase (BCKDK, a suppressor of BCKD) reduced BCAA/BCKA abundances and markedly attenuated IR in ob/ob mice. Similar outcomes were achieved by lowering protein (thus BCAAs) intake, while increasing BCAA intake did the opposite, corroborating the pathogenic roles of BCAA/BCKAs in IR in ob/ob mice. Like BCAAs, BCKAs also suppressed insulin signaling via mTORC1 activation. 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 BCAA catabolic defect and elevated BCAAs/BCKAs in obesity-associated IR and provide proof-of-concept evidence to the therapeutic validity of manipulating BCAA metabolism for treating diabetes.

PMID:
31167878
DOI:
10.2337/db18-0927

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center