RapamycinFungusV1, Main, Exploration, bibRecord, 000212

Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance.

Identifieur interne : 000212 ( Main/Exploration ); précédent : 000211; suivant : 000213

Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance.

Source :

Diabetes [ 1939-327X ] ; 2019.

RBID : pubmed:31167878

Descripteurs français

KwdFr :
- Acides aminés à chaine ramifiée (métabolisme), Alimentation riche en graisse (MeSH), Animaux (MeSH), Complexe-1 cible mécanistique de la rapamycine (métabolisme), Expression des gènes (MeSH), Humains (MeSH), Hyperglycémie provoquée (MeSH), Insuline (métabolisme), Insulinorésistance (physiologie), Mâle (MeSH), Métabolome (MeSH), Obésité (génétique), Obésité (métabolisme), Protein kinases (métabolisme), Souris (MeSH), Transduction du signal (physiologie), Étude d'association pangénomique (MeSH).
MESH :
- génétique : Obésité.
- métabolisme : Acides aminés à chaine ramifiée, Complexe-1 cible mécanistique de la rapamycine, Insuline, Obésité, Protein kinases.
- physiologie : Insulinorésistance, Transduction du signal.
- Alimentation riche en graisse, Animaux, Expression des gènes, Humains, Hyperglycémie provoquée, Mâle, Métabolome, Souris, Étude d'association pangénomique.

English descriptors

KwdEn :
- Amino Acids, Branched-Chain (metabolism), Animals (MeSH), Diet, High-Fat (MeSH), Gene Expression (MeSH), Genome-Wide Association Study (MeSH), Glucose Tolerance Test (MeSH), Humans (MeSH), Insulin (metabolism), Insulin Resistance (physiology), Male (MeSH), Mechanistic Target of Rapamycin Complex 1 (metabolism), Metabolome (MeSH), Mice (MeSH), Obesity (genetics), Obesity (metabolism), Protein Kinases (metabolism), Signal Transduction (physiology).
MESH :
- chemical , metabolism : Amino Acids, Branched-Chain, Insulin, Mechanistic Target of Rapamycin Complex 1, Protein Kinases.
- genetics : Obesity.
- metabolism : Obesity.
- physiology : Insulin Resistance, Signal Transduction.
- Animals, Diet, High-Fat, Gene Expression, Genome-Wide Association Study, Glucose Tolerance Test, Humans, Male, Metabolome, Mice.

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.

DOI: 10.2337/db18-0927
PubMed: 31167878
PubMed Central: PMC6702639

Affiliations:

Links toward previous steps (curation, corpus...)

to stream Main, to step Corpus: 000262
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Le document en format XML

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<sourceDesc><biblStruct><analytic><title xml:lang="en">Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance.</title>
<author><name sortKey="Zhou, Meiyi" sort="Zhou, Meiyi" uniqKey="Zhou M" first="Meiyi" last="Zhou">Meiyi Zhou</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai</wicri:regionArea>
<wicri:noRegion>Shanghai</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Shao, Jing" sort="Shao, Jing" uniqKey="Shao J" first="Jing" last="Shao">Jing Shao</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai</wicri:regionArea>
<wicri:noRegion>Shanghai</wicri:noRegion>
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<author><name sortKey="Wu, Cheng Yang" sort="Wu, Cheng Yang" uniqKey="Wu C" first="Cheng-Yang" last="Wu">Cheng-Yang Wu</name>
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<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Texas</region>
</placeName>
<wicri:cityArea>Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas</wicri:cityArea>
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<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Californie</region>
</placeName>
<wicri:cityArea>Department of Integrative Biology and Physiology, University of California at Los Angeles, Los Angeles</wicri:cityArea>
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<author><name sortKey="Dong, Weibing" sort="Dong, Weibing" uniqKey="Dong W" first="Weibing" last="Dong">Weibing Dong</name>
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<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai</wicri:regionArea>
<wicri:noRegion>Shanghai</wicri:noRegion>
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<author><name sortKey="Liu, Yunxia" sort="Liu, Yunxia" uniqKey="Liu Y" first="Yunxia" last="Liu">Yunxia Liu</name>
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<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai</wicri:regionArea>
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<author><name sortKey="Chen, Mengping" sort="Chen, Mengping" uniqKey="Chen M" first="Mengping" last="Chen">Mengping Chen</name>
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<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai</wicri:regionArea>
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<author><name sortKey="Wynn, R Max" sort="Wynn, R Max" uniqKey="Wynn R" first="R Max" last="Wynn">R Max Wynn</name>
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<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Texas</region>
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<author><name sortKey="Wang, Jiqiu" sort="Wang, Jiqiu" uniqKey="Wang J" first="Jiqiu" last="Wang">Jiqiu Wang</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai</wicri:regionArea>
<wicri:noRegion>Shanghai</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Wang, Ji" sort="Wang, Ji" uniqKey="Wang J" first="Ji" last="Wang">Ji Wang</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai</wicri:regionArea>
<wicri:noRegion>Shanghai</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Gui, Wen Jun" sort="Gui, Wen Jun" uniqKey="Gui W" first="Wen-Jun" last="Gui">Wen-Jun Gui</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Texas</region>
</placeName>
<wicri:cityArea>Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Qi, Xiangbing" sort="Qi, Xiangbing" uniqKey="Qi X" first="Xiangbing" last="Qi">Xiangbing Qi</name>
<affiliation wicri:level="3"><nlm:affiliation>Chemistry Center, National Institute of Biological Science, Beijing, China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Chemistry Center, National Institute of Biological Science, Beijing</wicri:regionArea>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lusis, Aldons J" sort="Lusis, Aldons J" uniqKey="Lusis A" first="Aldons J" last="Lusis">Aldons J. Lusis</name>
<affiliation wicri:level="2"><nlm:affiliation>Departments of Medicine, Microbiology, and Human Genetics, University of California at Los Angeles, Los Angeles, CA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Californie</region>
</placeName>
<wicri:cityArea>Departments of Medicine, Microbiology, and Human Genetics, University of California at Los Angeles, Los Angeles</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Li, Zhaoping" sort="Li, Zhaoping" uniqKey="Li Z" first="Zhaoping" last="Li">Zhaoping Li</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Clinical Nutrition, University of California at Los Angeles, Los Angeles, CA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Californie</region>
</placeName>
<wicri:cityArea>Department of Clinical Nutrition, University of California at Los Angeles, Los Angeles</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Wang, Weiqing" sort="Wang, Weiqing" uniqKey="Wang W" first="Weiqing" last="Wang">Weiqing Wang</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai</wicri:regionArea>
<wicri:noRegion>Shanghai</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Ning, Guang" sort="Ning, Guang" uniqKey="Ning G" first="Guang" last="Ning">Guang Ning</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai</wicri:regionArea>
<wicri:noRegion>Shanghai</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Yang, Xia" sort="Yang, Xia" uniqKey="Yang X" first="Xia" last="Yang">Xia Yang</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Integrative Biology and Physiology, University of California at Los Angeles, Los Angeles, CA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Californie</region>
</placeName>
<wicri:cityArea>Department of Integrative Biology and Physiology, University of California at Los Angeles, Los Angeles</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Chuang, David T" sort="Chuang, David T" uniqKey="Chuang D" first="David T" last="Chuang">David T. Chuang</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Texas</region>
</placeName>
<wicri:cityArea>Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Wang, Yibin" sort="Wang, Yibin" uniqKey="Wang Y" first="Yibin" last="Wang">Yibin Wang</name>
<affiliation wicri:level="2"><nlm:affiliation>Departments of Anesthesiology, Medicine, and Physiology, University of California at Los Angeles, Los Angeles, CA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Californie</region>
</placeName>
<wicri:cityArea>Departments of Anesthesiology, Medicine, and Physiology, University of California at Los Angeles, Los Angeles</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Sun, Haipeng" sort="Sun, Haipeng" uniqKey="Sun H" first="Haipeng" last="Sun">Haipeng Sun</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China sun.haipeng@yahoo.com.</nlm:affiliation>
<country wicri:rule="url">Oman</country>
<wicri:regionArea>Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai</wicri:regionArea>
<wicri:noRegion>Shanghai</wicri:noRegion>
</affiliation>
<affiliation wicri:level="2"><nlm:affiliation>Departments of Anesthesiology, Medicine, and Physiology, University of California at Los Angeles, Los Angeles, CA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Californie</region>
</placeName>
<wicri:cityArea>Departments of Anesthesiology, Medicine, and Physiology, University of California at Los Angeles, Los Angeles</wicri:cityArea>
</affiliation>
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<series><title level="j">Diabetes</title>
<idno type="eISSN">1939-327X</idno>
<imprint><date when="2019" type="published">2019</date>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acids, Branched-Chain (metabolism)</term>
<term>Animals (MeSH)</term>
<term>Diet, High-Fat (MeSH)</term>
<term>Gene Expression (MeSH)</term>
<term>Genome-Wide Association Study (MeSH)</term>
<term>Glucose Tolerance Test (MeSH)</term>
<term>Humans (MeSH)</term>
<term>Insulin (metabolism)</term>
<term>Insulin Resistance (physiology)</term>
<term>Male (MeSH)</term>
<term>Mechanistic Target of Rapamycin Complex 1 (metabolism)</term>
<term>Metabolome (MeSH)</term>
<term>Mice (MeSH)</term>
<term>Obesity (genetics)</term>
<term>Obesity (metabolism)</term>
<term>Protein Kinases (metabolism)</term>
<term>Signal Transduction (physiology)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Acides aminés à chaine ramifiée (métabolisme)</term>
<term>Alimentation riche en graisse (MeSH)</term>
<term>Animaux (MeSH)</term>
<term>Complexe-1 cible mécanistique de la rapamycine (métabolisme)</term>
<term>Expression des gènes (MeSH)</term>
<term>Humains (MeSH)</term>
<term>Hyperglycémie provoquée (MeSH)</term>
<term>Insuline (métabolisme)</term>
<term>Insulinorésistance (physiologie)</term>
<term>Mâle (MeSH)</term>
<term>Métabolome (MeSH)</term>
<term>Obésité (génétique)</term>
<term>Obésité (métabolisme)</term>
<term>Protein kinases (métabolisme)</term>
<term>Souris (MeSH)</term>
<term>Transduction du signal (physiologie)</term>
<term>Étude d'association pangénomique (MeSH)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Amino Acids, Branched-Chain</term>
<term>Insulin</term>
<term>Mechanistic Target of Rapamycin Complex 1</term>
<term>Protein Kinases</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Obesity</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Obésité</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Obesity</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Acides aminés à chaine ramifiée</term>
<term>Complexe-1 cible mécanistique de la rapamycine</term>
<term>Insuline</term>
<term>Obésité</term>
<term>Protein kinases</term>
</keywords>
<keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Insulinorésistance</term>
<term>Transduction du signal</term>
</keywords>
<keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Insulin Resistance</term>
<term>Signal Transduction</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Diet, High-Fat</term>
<term>Gene Expression</term>
<term>Genome-Wide Association Study</term>
<term>Glucose Tolerance Test</term>
<term>Humans</term>
<term>Male</term>
<term>Metabolome</term>
<term>Mice</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Alimentation riche en graisse</term>
<term>Animaux</term>
<term>Expression des gènes</term>
<term>Humains</term>
<term>Hyperglycémie provoquée</term>
<term>Mâle</term>
<term>Métabolome</term>
<term>Souris</term>
<term>Étude d'association pangénomique</term>
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<front><div type="abstract" xml:lang="en">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 (<i>ob/ob</i>
) 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 <i>ob/ob</i>
 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 <i>ob/ob</i>
 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.</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">31167878</PMID>
<DateCompleted><Year>2020</Year>
<Month>03</Month>
<Day>20</Day>
</DateCompleted>
<DateRevised><Year>2020</Year>
<Month>09</Month>
<Day>02</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1939-327X</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>68</Volume>
<Issue>9</Issue>
<PubDate><Year>2019</Year>
<Month>09</Month>
</PubDate>
</JournalIssue>
<Title>Diabetes</Title>
<ISOAbbreviation>Diabetes</ISOAbbreviation>
</Journal>
<ArticleTitle>Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance.</ArticleTitle>
<Pagination><MedlinePgn>1730-1746</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.2337/db18-0927</ELocationID>
<Abstract><AbstractText>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 (<i>ob/ob</i>
) 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 <i>ob/ob</i>
 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 <i>ob/ob</i>
 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.</AbstractText>
<CopyrightInformation>© 2019 by the American Diabetes Association.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Zhou</LastName>
<ForeName>Meiyi</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Shao</LastName>
<ForeName>Jing</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Wu</LastName>
<ForeName>Cheng-Yang</ForeName>
<Initials>CY</Initials>
<AffiliationInfo><Affiliation>Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Shu</LastName>
<ForeName>Le</ForeName>
<Initials>L</Initials>
<AffiliationInfo><Affiliation>Department of Integrative Biology and Physiology, University of California at Los Angeles, Los Angeles, CA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Dong</LastName>
<ForeName>Weibing</ForeName>
<Initials>W</Initials>
<AffiliationInfo><Affiliation>Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Liu</LastName>
<ForeName>Yunxia</ForeName>
<Initials>Y</Initials>
<AffiliationInfo><Affiliation>Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Chen</LastName>
<ForeName>Mengping</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Wynn</LastName>
<ForeName>R Max</ForeName>
<Initials>RM</Initials>
<Identifier Source="ORCID">0000-0002-1879-2136</Identifier>
<AffiliationInfo><Affiliation>Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Wang</LastName>
<ForeName>Jiqiu</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Wang</LastName>
<ForeName>Ji</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Gui</LastName>
<ForeName>Wen-Jun</ForeName>
<Initials>WJ</Initials>
<AffiliationInfo><Affiliation>Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Qi</LastName>
<ForeName>Xiangbing</ForeName>
<Initials>X</Initials>
<AffiliationInfo><Affiliation>Chemistry Center, National Institute of Biological Science, Beijing, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Lusis</LastName>
<ForeName>Aldons J</ForeName>
<Initials>AJ</Initials>
<Identifier Source="ORCID">0000-0001-9013-0228</Identifier>
<AffiliationInfo><Affiliation>Departments of Medicine, Microbiology, and Human Genetics, University of California at Los Angeles, Los Angeles, CA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Li</LastName>
<ForeName>Zhaoping</ForeName>
<Initials>Z</Initials>
<AffiliationInfo><Affiliation>Department of Clinical Nutrition, University of California at Los Angeles, Los Angeles, CA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Wang</LastName>
<ForeName>Weiqing</ForeName>
<Initials>W</Initials>
<AffiliationInfo><Affiliation>Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ning</LastName>
<ForeName>Guang</ForeName>
<Initials>G</Initials>
<AffiliationInfo><Affiliation>Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Yang</LastName>
<ForeName>Xia</ForeName>
<Initials>X</Initials>
<Identifier Source="ORCID">0000-0002-3971-038X</Identifier>
<AffiliationInfo><Affiliation>Department of Integrative Biology and Physiology, University of California at Los Angeles, Los Angeles, CA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Chuang</LastName>
<ForeName>David T</ForeName>
<Initials>DT</Initials>
<Identifier Source="ORCID">0000-0002-3640-8927</Identifier>
<AffiliationInfo><Affiliation>Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Wang</LastName>
<ForeName>Yibin</ForeName>
<Initials>Y</Initials>
<AffiliationInfo><Affiliation>Departments of Anesthesiology, Medicine, and Physiology, University of California at Los Angeles, Los Angeles, CA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Sun</LastName>
<ForeName>Haipeng</ForeName>
<Initials>H</Initials>
<Identifier Source="ORCID">0000-0003-2128-3209</Identifier>
<AffiliationInfo><Affiliation>Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China sun.haipeng@yahoo.com.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Departments of Anesthesiology, Medicine, and Physiology, University of California at Los Angeles, Los Angeles, CA.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<GrantList CompleteYN="Y"><Grant><GrantID>R56 DK062306</GrantID>
<Acronym>DK</Acronym>
<Agency>NIDDK NIH HHS</Agency>
<Country>United States</Country>
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<Month>06</Month>
<Day>05</Day>
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<MedlineTA>Diabetes</MedlineTA>
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<ISSNLinking>0012-1797</ISSNLinking>
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	Serveur d'exploration sur la rapamycine et les champignons
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Serveur d'exploration sur la rapamycine et les champignons

Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance.

Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance.

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