Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity

Denise E. Lackey, Christopher J. Lynch, Kristine C. Olson, Rouzbeh Mostaedi, Mohamed R Ali, William H. Smith, Fredrik Karpe, Sandy Humphreys, Daniel H. Bedinger, Tamara N. Dunn, Anthony P. Thomas, Pieter J. Oort, Dorothy A. Kieffer, Rajesh Amin, Ahmed Bettaieb, Fawaz Haj, Paska Permana, Tracy G. Anthony, Sean H. Adams

Research output: Contribution to journalArticle

142 Scopus citations

Abstract

Elevated blood branched-chain amino acids (BCAA) are often associated with insulin resistance and type 2 diabetes, which might result from a reduced cellular utilization and/or incomplete BCAA oxidation. White adipose tissue (WAT) has become appreciated as a potential player in whole body BCAA metabolism. We tested if expression of the mitochondrial BCAA oxidation checkpoint, branched-chain α-ketoacid dehydrogenase (BCKD) complex, is reduced in obese WAT and regulated by metabolic signals. WAT BCKD protein (E1α subunit) was significantly reduced by 35-50% in various obesity models (fa/fa rats, db/db mice, diet-induced obese mice), and BCKD component transcripts significantly lower in subcutaneous (SC) adipocytes from obese vs. lean Pima Indians. Treatment of 3T3-L1 adipocytes or mice with peroxisome proliferatoractivated receptor-γ agonists increased WAT BCAA catabolism enzyme mRNAs, whereas the nonmetabolizable glucose analog 2-deoxy-D-glucose had the opposite effect. The results support the hypothesis that suboptimal insulin action and/or perturbed metabolic signals in WAT, as would be seen with insulin resistance/type 2 diabetes, could impair WAT BCAA utilization. However, cross-tissue flux studies comparing lean vs. insulin-sensitive or insulin-resistant obese subjects revealed an unexpected negligible uptake of BCAA from human abdominal SC WAT. This suggests that SC WAT may not be an important contributor to blood BCAA phenotypes associated with insulin resistance in the overnight-fasted state. mRNA abundances for BCAA catabolic enzymes were markedly reduced in omental (but not SC) WAT of obese persons with metabolic syndrome compared with weight-matched healthy obese subjects, raising the possibility that visceral WAT contributes to the BCAA metabolic phenotype of metabolically compromised individuals.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume304
Issue number11
DOIs
StatePublished - Jun 1 2013

Keywords

  • Bariatric
  • Diabetes
  • Hyperinsulinemia
  • Mammalian target of rapamycin
  • Protein

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism

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    Lackey, D. E., Lynch, C. J., Olson, K. C., Mostaedi, R., Ali, M. R., Smith, W. H., Karpe, F., Humphreys, S., Bedinger, D. H., Dunn, T. N., Thomas, A. P., Oort, P. J., Kieffer, D. A., Amin, R., Bettaieb, A., Haj, F., Permana, P., Anthony, T. G., & Adams, S. H. (2013). Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity. American Journal of Physiology - Endocrinology and Metabolism, 304(11). https://doi.org/10.1152/ajpendo.00630.2012