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

Author
item Lackey, Denise - University Of California
item Lynch, Christopher - Pennsylvania State University
item Olson, Kristine - Pennsylvania State University
item Mostaedi, Rouzbeh - University Of California
item Ali, Mohamed - University Of California
item Smith, William - University Of California
item Humphreys, Sandy - Oxford Radcliffe Hospitals
item Bedinger, Daniel - University Of California
item Dunn, Tamara - University Of California
item Thomas, Anthony - University Of California
item Oort, Pieter
item Kieffer, Dorothy - University Of California
item Amin, Rajesh - Auburn State University
item Bettaieb, Ahmed - University Of California
item Haj, Fawaz - University Of California
item Permana, Paska - Veterans Affairs Medical Center - Phoenix
item Anthony, Tracy - Rutgers University
item Adams, Sean

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Review Article
Publication Acceptance Date: 1/2/2013
Publication Date: 3/19/2013
Citation: Lackey, D.E., Lynch, C.J., Olson, K.C., Mostaedi, R., Ali, M., Smith, W.H., Humphreys, S., Bedinger, D.H., Dunn, T.N., Thomas, A.P., Oort, P.J., Kieffer, D.A., Amin, R., Bettaieb, A., Haj, F.G., Permana, P., Anthony, T.G., Adams, S.H. 2013. Regulation of adipose branched-chain amin acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity. American Journal of Physiology - Endocrinology and Metabolism. 304:e1175-e1187. doi: 10.1152/AJPENDO.00630.2012.

Interpretive Summary: Elevated blood branched-chain amin acids (BCAA)are often assoicated with insulin resistance and type2 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 a-ketoacid dehydrohgenase (BCKD) complex, is reduced in obese WAT and regulated by metabolic signals. WATBCKD protein (Ela subunit) was significantly reduced by 35-50% invarious 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 proliferator-activated receptors-g agonists increased WAT BCAA catabolism enzyme mRNAs, whereas, the nonmetabolizable glucose analog 2-deoxy-d-glucose had the opposite effect. The resuklts support the hypothesis that suboptimal insulin action and/or perturbed metabolic signals in WAT, as would be seen with insulin resistance/type 2diabetes, could impair WAT BCAA utilization. However, cross-tissue flux studeis in WAT, as would be seen with insulin-sensitive or insulin-resistantobese subjects revealed an unexpected negligible uptake of BCAA fromhuman abdominal SC WAT. This suggests that SC WAT may not be an important contriutor to blodd 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 visceal WAT contributes to the BCAA metabolic phenotype of metabollically compromised individuals.

Technical Abstract: Elevated blood branched-chain amin acids (BCAA)are often assoicated with insulin resistance and type2 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 a-ketoacid dehydrohgenase (BCKD) complex, is reduced in obese WAT and regulated by metabolic signals. WATBCKD protein (Ela subunit) was significantly reduced by 35-50% invarious 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 proliferator-activated receptors-g agonists increased WAT BCAA catabolism enzyme mRNAs, whereas, the nonmetabolizable glucose analog 2-deoxy-d-glucose had the opposite effect. The resuklts support the hypothesis that suboptimal insulin action and/or perturbed metabolic signals in WAT, as would be seen with insulin resistance/type 2diabetes, could impair WAT BCAA utilization. However, cross-tissue flux studeis in WAT, as would be seen with insulin-sensitive or insulin-resistantobese subjects revealed an unexpected negligible uptake of BCAA fromhuman abdominal SC WAT. This suggests that SC WAT may not be an important contriutor to blodd 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 visceal WAT contributes to the BCAA metabolic phenotype of metabollically compromised individuals.