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Branched-Chain Amino Acid Catabolism in Skeletal Muscle Controls Systemic BCAA Levels Without Impacting Insulin Resistance- [electronic resource]
Branched-Chain Amino Acid Catabolism in Skeletal Muscle Controls Systemic BCAA Levels Without Impacting Insulin Resistance- [electronic resource]
상세정보
- 자료유형
- 학위논문파일 국외
- 최종처리일시
- 20240214100126
- ISBN
- 9798379755874
- DDC
- 574
- 저자명
- Blair, Megan C.
- 서명/저자
- Branched-Chain Amino Acid Catabolism in Skeletal Muscle Controls Systemic BCAA Levels Without Impacting Insulin Resistance - [electronic resource]
- 발행사항
- [S.l.]: : University of Pennsylvania., 2023
- 발행사항
- Ann Arbor : : ProQuest Dissertations & Theses,, 2023
- 형태사항
- 1 online resource(114 p.)
- 주기사항
- Source: Dissertations Abstracts International, Volume: 85-01, Section: B.
- 주기사항
- Advisor: Arany, Zoltan Pierre;Wellen, Kathryn E.
- 학위논문주기
- Thesis (Ph.D.)--University of Pennsylvania, 2023.
- 사용제한주기
- This item must not be sold to any third party vendors.
- 초록/해제
- 요약Elevated plasma branched-chain amino acids (BCAAs) have been associated with type 2 diabetes since the 1960s. Pharmacological activation of branched-chain α-ketoacid dehydrogenase (BCKDH), the rate-limiting enzyme of BCAA oxidation, lowers plasma BCAAs and improves glucose tolerance in both rodents and humans. However, how BCAA oxidation alleviates insulin resistance, and through which tissues, remains unclear. To address these questions, we developed skeletal muscle and liver-specific BCKDH gain-of-function and loss-of-function mouse models, and comprehensively evaluated glucose homeostasis. We found that altered BCAA oxidation in neither skeletal muscle nor liver, alone or in combination, is sufficient to improve or worsen insulin sensitivity in male mice fed chow or high-fat diet. Modulation of BCKDH activity in skeletal muscle, but not liver, affected fasting plasma BCAAs. However, despite lowering systemic BCAA levels, skeletal muscle-specific increase in BCAA oxidation did not improve insulin sensitivity. These data show that skeletal muscle controls plasma BCAAs, that lowering fasting plasma BCAAs is insufficient to improve insulin sensitivity, and that neither skeletal muscle nor liver account for the improved insulin sensitivity seen with pharmacological activation of BCKDH. Our findings suggest concerted contributions of multiple tissues in the modulation of BCAA metabolism to alter insulin sensitivity.
- 일반주제명
- Molecular biology.
- 일반주제명
- Cellular biology.
- 일반주제명
- Physiology.
- 키워드
- BCAA oxidation
- 기타저자
- University of Pennsylvania Cell and Molecular Biology
- 기본자료저록
- Dissertations Abstracts International. 85-01B.
- 기본자료저록
- Dissertation Abstract International
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520240214100126
■006m o d
■007cr#unu||||||||
■020 ▼a9798379755874
■035 ▼a(MiAaPQ)AAI30425439
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aBlair, Megan C.
■24510▼aBranched-Chain Amino Acid Catabolism in Skeletal Muscle Controls Systemic BCAA Levels Without Impacting Insulin Resistance▼h[electronic resource]
■260 ▼a[S.l.]:▼bUniversity of Pennsylvania. ▼c2023
■260 1▼aAnn Arbor :▼bProQuest Dissertations & Theses, ▼c2023
■300 ▼a1 online resource(114 p.)
■500 ▼aSource: Dissertations Abstracts International, Volume: 85-01, Section: B.
■500 ▼aAdvisor: Arany, Zoltan Pierre;Wellen, Kathryn E.
■5021 ▼aThesis (Ph.D.)--University of Pennsylvania, 2023.
■506 ▼aThis item must not be sold to any third party vendors.
■520 ▼aElevated plasma branched-chain amino acids (BCAAs) have been associated with type 2 diabetes since the 1960s. Pharmacological activation of branched-chain α-ketoacid dehydrogenase (BCKDH), the rate-limiting enzyme of BCAA oxidation, lowers plasma BCAAs and improves glucose tolerance in both rodents and humans. However, how BCAA oxidation alleviates insulin resistance, and through which tissues, remains unclear. To address these questions, we developed skeletal muscle and liver-specific BCKDH gain-of-function and loss-of-function mouse models, and comprehensively evaluated glucose homeostasis. We found that altered BCAA oxidation in neither skeletal muscle nor liver, alone or in combination, is sufficient to improve or worsen insulin sensitivity in male mice fed chow or high-fat diet. Modulation of BCKDH activity in skeletal muscle, but not liver, affected fasting plasma BCAAs. However, despite lowering systemic BCAA levels, skeletal muscle-specific increase in BCAA oxidation did not improve insulin sensitivity. These data show that skeletal muscle controls plasma BCAAs, that lowering fasting plasma BCAAs is insufficient to improve insulin sensitivity, and that neither skeletal muscle nor liver account for the improved insulin sensitivity seen with pharmacological activation of BCKDH. Our findings suggest concerted contributions of multiple tissues in the modulation of BCAA metabolism to alter insulin sensitivity.
■590 ▼aSchool code: 0175.
■650 4▼aMolecular biology.
■650 4▼aCellular biology.
■650 4▼aPhysiology.
■653 ▼aAmino acid catabolism
■653 ▼aBCAA oxidation
■653 ▼aInsulin resistance
■653 ▼aPharmacological activation
■690 ▼a0307
■690 ▼a0379
■690 ▼a0719
■71020▼aUniversity of Pennsylvania▼bCell and Molecular Biology.
■7730 ▼tDissertations Abstracts International▼g85-01B.
■773 ▼tDissertation Abstract International
■790 ▼a0175
■791 ▼aPh.D.
■792 ▼a2023
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T16931846▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
■980 ▼a202402▼f2024
