Targeting BCAA catabolism to treat obesity-associated insulin resistance

Meiyi Zhou, Jing Shao, Cheng Yang Wu, Le Shu, Weibing Dong, Yunxia Liu, Mengping Chen, Richard M Wynn, Jiqiu Wang, Ji Wang, Wen Jun Gui, Xiangbing Qi, Aldons J. Lusis, Zhaoping Li, Weiqing Wang, Guang Ning, Xia Yang, David T Chuang, Yibin Wang, Haipeng Sun

Research output: Contribution to journalArticle

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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 obesityassociated 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 a-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 outcomeswere 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-ofconcept evidence for the therapeutic validity of manipulating BCAA metabolism for treating diabetes.

Original languageEnglish (US)
Pages (from-to)1730-1746
Number of pages17
JournalDiabetes
Volume68
Issue number9
DOIs
StatePublished - Sep 1 2019

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Branched Chain Amino Acids
Insulin Resistance
Obesity
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
Keto Acids
Obese Mice
High Fat Diet

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Zhou, M., Shao, J., Wu, C. Y., Shu, L., Dong, W., Liu, Y., ... Sun, H. (2019). Targeting BCAA catabolism to treat obesity-associated insulin resistance. Diabetes, 68(9), 1730-1746. https://doi.org/10.2337/db18-0927

Targeting BCAA catabolism to treat obesity-associated insulin resistance. / Zhou, Meiyi; Shao, Jing; Wu, Cheng Yang; Shu, Le; Dong, Weibing; Liu, Yunxia; Chen, Mengping; Wynn, Richard M; Wang, Jiqiu; Wang, Ji; Gui, Wen Jun; Qi, Xiangbing; Lusis, Aldons J.; Li, Zhaoping; Wang, Weiqing; Ning, Guang; Yang, Xia; Chuang, David T; Wang, Yibin; Sun, Haipeng.

In: Diabetes, Vol. 68, No. 9, 01.09.2019, p. 1730-1746.

Research output: Contribution to journalArticle

Zhou, M, Shao, J, Wu, CY, Shu, L, Dong, W, Liu, Y, Chen, M, Wynn, RM, Wang, J, Wang, J, Gui, WJ, Qi, X, Lusis, AJ, Li, Z, Wang, W, Ning, G, Yang, X, Chuang, DT, Wang, Y & Sun, H 2019, 'Targeting BCAA catabolism to treat obesity-associated insulin resistance', Diabetes, vol. 68, no. 9, pp. 1730-1746. https://doi.org/10.2337/db18-0927
Zhou M, Shao J, Wu CY, Shu L, Dong W, Liu Y et al. Targeting BCAA catabolism to treat obesity-associated insulin resistance. Diabetes. 2019 Sep 1;68(9):1730-1746. https://doi.org/10.2337/db18-0927
Zhou, Meiyi ; Shao, Jing ; Wu, Cheng Yang ; Shu, Le ; Dong, Weibing ; Liu, Yunxia ; Chen, Mengping ; Wynn, Richard M ; Wang, Jiqiu ; Wang, Ji ; Gui, Wen Jun ; Qi, Xiangbing ; Lusis, Aldons J. ; Li, Zhaoping ; Wang, Weiqing ; Ning, Guang ; Yang, Xia ; Chuang, David T ; Wang, Yibin ; Sun, Haipeng. / Targeting BCAA catabolism to treat obesity-associated insulin resistance. In: Diabetes. 2019 ; Vol. 68, No. 9. pp. 1730-1746.
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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 obesityassociated 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 a-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 outcomeswere 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-ofconcept evidence for the therapeutic validity of manipulating BCAA metabolism for treating diabetes.",
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AU - Chen, Mengping

AU - Wynn, Richard M

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AU - Gui, Wen Jun

AU - Qi, Xiangbing

AU - Lusis, Aldons J.

AU - Li, Zhaoping

AU - Wang, Weiqing

AU - Ning, Guang

AU - Yang, Xia

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