TY - JOUR
T1 - Quantitative Analysis of the Whole-Body Metabolic Fate of Branched-Chain Amino Acids
AU - Neinast, Michael D.
AU - Jang, Cholsoon
AU - Hui, Sheng
AU - Murashige, Danielle S.
AU - Chu, Qingwei
AU - Morscher, Raphael J.
AU - Li, Xiaoxuan
AU - Zhan, Le
AU - White, Eileen
AU - Anthony, Tracy G.
AU - Rabinowitz, Joshua D.
AU - Arany, Zoltan
N1 - Funding Information:
C.J. is a postdoctoral fellow of the American Diabetes Association (1-17-PDF-076). S.H. is a Merck Fellow of the Life Sciences Research Foundation. This work was supported by grants from the NIH ( T32-GM07229 to M.D.N., DK109714 to T.G.A., and HL094499 and DK107667 to Z.A.), support from the DRC Regional Metabolomics Core ( P30 DK19525 ), and an Established Investigator Award from the American Heart Association (Z.A.). We thank Emily Mirek in the Anthony lab for technical support, and members of the Arany lab and the Rabinowitz lab, Mitchel Lazar, William Quinn, and Joseph Baur for scientific discussions.
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2019/2/5
Y1 - 2019/2/5
N2 - Elevations in branched-chain amino acids (BCAAs) associate with numerous systemic diseases, including cancer, diabetes, and heart failure. However, an integrated understanding of whole-body BCAA metabolism remains lacking. Here, we employ in vivo isotopic tracing to systemically quantify BCAA oxidation in healthy and insulin-resistant mice. We find that most tissues rapidly oxidize BCAAs into the tricarboxylic acid (TCA) cycle, with the greatest quantity occurring in muscle, brown fat, liver, kidneys, and heart. Notably, pancreas supplies 20% of its TCA carbons from BCAAs. Genetic and pharmacologic suppression of branched-chain alpha-ketoacid dehydrogenase kinase, a clinically targeted regulatory kinase, induces BCAA oxidation primarily in skeletal muscle of healthy mice. While insulin acutely increases BCAA oxidation in cardiac and skeletal muscle, chronically insulin-resistant mice show blunted BCAA oxidation in adipose tissues and liver, shifting BCAA oxidation toward muscle. Together, this work provides a quantitative framework for understanding systemic BCAA oxidation in health and insulin resistance.
AB - Elevations in branched-chain amino acids (BCAAs) associate with numerous systemic diseases, including cancer, diabetes, and heart failure. However, an integrated understanding of whole-body BCAA metabolism remains lacking. Here, we employ in vivo isotopic tracing to systemically quantify BCAA oxidation in healthy and insulin-resistant mice. We find that most tissues rapidly oxidize BCAAs into the tricarboxylic acid (TCA) cycle, with the greatest quantity occurring in muscle, brown fat, liver, kidneys, and heart. Notably, pancreas supplies 20% of its TCA carbons from BCAAs. Genetic and pharmacologic suppression of branched-chain alpha-ketoacid dehydrogenase kinase, a clinically targeted regulatory kinase, induces BCAA oxidation primarily in skeletal muscle of healthy mice. While insulin acutely increases BCAA oxidation in cardiac and skeletal muscle, chronically insulin-resistant mice show blunted BCAA oxidation in adipose tissues and liver, shifting BCAA oxidation toward muscle. Together, this work provides a quantitative framework for understanding systemic BCAA oxidation in health and insulin resistance.
KW - branched chain amino acids
KW - insulin resistance
KW - obesity
KW - stable isotope tracing
UR - http://www.scopus.com/inward/record.url?scp=85060699237&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85060699237&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2018.10.013
DO - 10.1016/j.cmet.2018.10.013
M3 - Article
C2 - 30449684
AN - SCOPUS:85060699237
SN - 1550-4131
VL - 29
SP - 417-429.e4
JO - Cell Metabolism
JF - Cell Metabolism
IS - 2
ER -