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Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance

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 thi...

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Autores principales: Zhou, Meiyi, Shao, Jing, Wu, Cheng-Yang, Shu, Le, Dong, Weibing, Liu, Yunxia, Chen, Mengping, Wynn, R. Max, 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702639/
https://www.ncbi.nlm.nih.gov/pubmed/31167878
http://dx.doi.org/10.2337/db18-0927
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author Zhou, Meiyi
Shao, Jing
Wu, Cheng-Yang
Shu, Le
Dong, Weibing
Liu, Yunxia
Chen, Mengping
Wynn, R. Max
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
author_facet Zhou, Meiyi
Shao, Jing
Wu, Cheng-Yang
Shu, Le
Dong, Weibing
Liu, Yunxia
Chen, Mengping
Wynn, R. Max
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
author_sort Zhou, Meiyi
collection PubMed
description 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.
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spelling pubmed-67026392020-09-01 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, R. Max 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 Diabetes Metabolism 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. American Diabetes Association 2019-09 2019-08-14 /pmc/articles/PMC6702639/ /pubmed/31167878 http://dx.doi.org/10.2337/db18-0927 Text en © 2019 by the American Diabetes Association. http://www.diabetesjournals.org/content/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.
spellingShingle Metabolism
Zhou, Meiyi
Shao, Jing
Wu, Cheng-Yang
Shu, Le
Dong, Weibing
Liu, Yunxia
Chen, Mengping
Wynn, R. Max
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
title Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance
title_full Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance
title_fullStr Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance
title_full_unstemmed Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance
title_short Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance
title_sort targeting bcaa catabolism to treat obesity-associated insulin resistance
topic Metabolism
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702639/
https://www.ncbi.nlm.nih.gov/pubmed/31167878
http://dx.doi.org/10.2337/db18-0927
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