title: Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity.
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 proliferator-activated 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.
authors.affiliation: Obesity & Metabolism Research Unit, United States Department of Agriculture-Agricultural Research Service Western Human Nutrition Research Center, Davis, CA 95616, USA. dlackey@ucsd.edu
authors.forename: Denise E
authors.initials: DE
authors.lastname: Lackey
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lynch
authors.forename: Kristine C
authors.initials: KC
authors.lastname: Olson
authors.forename: Rouzbeh
authors.initials: R
authors.lastname: Mostaedi
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ali
authors.forename: William H
authors.initials: WH
authors.lastname: Smith
authors.forename: Fredrik
authors.initials: F
authors.lastname: Karpe
authors.forename: Sandy
authors.initials: S
authors.lastname: Humphreys
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Bedinger
authors.forename: Tamara N
authors.initials: TN
authors.lastname: Dunn
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Thomas
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Oort
authors.forename: Dorothy A
authors.initials: DA
authors.lastname: Kieffer
authors.forename: Rajesh
authors.initials: R
authors.lastname: Amin
authors.forename: Ahmed
authors.initials: A
authors.lastname: Bettaieb
authors.forename: Fawaz G
authors.initials: FG
authors.lastname: Haj
authors.forename: Paska
authors.initials: P
authors.lastname: Permana
authors.forename: Tracy G
authors.initials: TG
authors.lastname: Anthony
authors.forename: Sean H
authors.initials: SH
authors.lastname: Adams
mesh_terms: D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / Q000378:metabolism*; D017667:Adipocytes / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism*; D000328:Adult; D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood; D051379:Mice; D008820:Mice, Obese; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker
chemical_list: D000597:Amino Acids, Branched-Chain; D007328:Insulin; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
keywords: bariatric; diabetes; hyperinsulinemia; mammalian target of rapamycin; protein