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

Authors: Lackey, Denise; LYNCH, CHRISTOPHER - Pennsylvania State University; OLSON, KRISTINE - Pennsylvania State University; MOSTAEDI, ROUZBEH - University Of California; ALI, MOHAMED - University Of California; SMITH, WILLIAM - University Of California; KARPE, FREDRIK - University Of Oxford; HUMPHREYS, SANDY - University Of Oxford; BEDINGER, DANIEL - University Of California; DUNN, TAMARA - University Of California; THOMAS, ANTHONY - University Of California; Oort, Pieter; KIEFFER, DOROTHY - University Of California; AMIN, RAJESH - Auburn State University; BETTAIEB, AHMED - University Of California; HAJ, FAWAZ - University Of California; PERMANA, PASKA - Veterans Affairs Medical Center - Phoenix; ANTHONY, TRACY - Rutgers University; Adams, Sean

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/13/2013
Publication Date: 3/19/2013
Citation: Lackey, D.E., Lynch, C.J., Olson, K.C., Mostaedi, R., Ali, M., 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.G., 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: E1175-E1187. DOI: 10.1152/ajpendo.006302012.

Interpretive Summary: Elevated blood branched chain amino acids (BCAA, part of a group of essential amino acids that are supplied to the body through food proteins) are often associated with insulin resistance and type 2 diabetes. One possibility is that under these conditions there is a reduced cellular utilization and/or lower complete oxidation of BCAAs for energy. Interestingly, fat tissue has recently become appreciated as an important player in whole-body BCAA metabolism, and so the amount of body fat could impact overall blood concentrations including the BCAA. The current studies tested if expression of the mitochondrial BCAA oxidation check-point, the branched chain a-ketoacid dehydrogenase (BCKD) complex, is reduced in rodent and human fat tissue in obesity and regulated by metabolic signals. Fat tissue BCKD protein was significantly reduced by 35-50% in monogenic obesity models (fa/fa rats and db/db mice) and in diet-induced obese mice. Gene transcripts for BCKD components were significantly lower in isolated subcutaneous (SC) adipocytes (fat cells) from obese vs. lean Pima Indians, and reduced in omental fat (internal, visceral fat) of obese subjects with metabolic syndrome compared to equally-obese healthy controls. Treatment of maturing 3T3-L1 fat cells with anti-diabetic PPAR' activating molecules generally increased BCAA catabolism enzyme gene expression, whereas the non-metabolizable glucose analogue 2-deoxy-D-glucose had the opposite effect. Novel proof-of-principle studies revealed an unexpected net efflux of BCAA from human SC fat tissue, which in absolute terms was 500% and 100% higher in obese insulin-resistant individuals compared to obese and lean insulin-sensitive individuals, respectively. Overall, the results support the hypothesis that perturbed metabolic signals in WAT, as would be seen with insulin resistance, pre-diabetes or type 2 diabetes, can act to lower fat tissue BCKD expression and impair BCAA utilization in this tissue.

Technical Abstract: Elevated blood branched chain amino acids (BCAA) are often associated with insulin resistance and type 2 diabetes. One possibility is that under these conditions there is a reduced cellular utilization and/or lower complete oxidation of BCAAs. White adipose tissue (WAT) has become appreciated as an important player in whole-body BCAA metabolism. The current studies tested if expression of the mitochondrial BCAA oxidation check-point, the branched chain a-ketoacid dehydrogenase (BCKD) complex, is reduced in rodent and human WAT in obesity and regulated by metabolic signals. WAT BCKD protein was significantly reduced by 35-50% in monogenic obesity models (fa/fa rats and db/db mice) and in diet-induced obese mice. Transcripts for BCKD components were significantly lower in isolated subcutaneous (SC) adipocytes from obese vs. lean Pima Indians, and reduced in omental WAT of obese subjects with metabolic syndrome compared to equally-obese healthy controls. Treatment of maturing 3T3-L1 adipocytes with PPAR' agonists generally increased BCAA catabolism enzyme mRNAs, whereas the non-metabolizable glucose analogue 2-deoxy-D-glucose had the opposite effect. Novel proof-of-principle studies revealed an unexpected net efflux of BCAA from human SC WAT, which in absolute terms was 500% and 100% higher in obese insulin-resistant individuals compared to obese and lean insulin-sensitive individuals, respectively. However, person-to-person variability was high and differences did not achieve statistical significance. Overall, the results support the hypothesis that sub-optimal insulin action and/or perturbed metabolic signals in WAT, as would be seen with insulin resistance or type 2 diabetes, act to lower WAT BCKD expression and impair WAT BCAA utilization.