Wiley Interdiscip Rev Syst Biol Med. 2013 Jul-Aug;5(4):449-60. Epub 2013 Mar 29.Mattick JS1, Kamisoglu K, Ierapetritou MG, Androulakis IP, Berthiaume F.Author information1Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.AbstractThe changes that occur in mammalian systems following trauma and sepsis, termed systemic inflammatory response syndrome, elicit major changes in carbohydrate, protein, and energy metabolism. When these events persist for too long they result in a severe depletion of lean body mass, multiple organ dysfunction, and eventually death. Nutritional supplementation has been investigated to offset the severe loss of protein, and recent evidence suggests that diets enriched in branched-chain amino acids (BCAAs) may be especially beneficial. BCAAs are metabolized in two major steps that are differentially expressed in muscle and liver. In muscle, BCAAs are reversibly transaminated to the corresponding α-keto acids.
Central Canada - Author ManuscriptMiscellaneousNCI CPTC Antibody Characterization ProgramWe're sorry...... but your computer or network may be sending automated queries. To protect our users, we can't process your request right now.See Google Help for more information.Please, wait while we are validating your browserBranched-chain amino acids (BCAAs) are important nutrient signals that have direct and indirect effects. Frequently, BCAAs have been reported to mediate antiobesity effects, especially in rodent models. However, circulating levels of BCAAs tend to be increased in individuals with obesity and are associated with worse metabolic health and future insulin resistance or type 2 diabetes mellitus (T2DM). A hypothesized mechanism linking increased levels of BCAAs and T2DM involves leucine-mediated activation of the mammalian target of rapamycin complex 1 (mTORC1), which results in uncoupling of insulin signalling at an early stage. A BCAA dysmetabolism model proposes that the accumulation of mitotoxic metabolites (and not BCAAs per se) promotes β-cell mitochondrial dysfunction, stress signalling and apoptosis associated with T2DM.
Alternatively, insulin resistance might promote aminoacidaemia by increasing the protein degradation that insulin normally suppresses, and/or by eliciting an impairment of efficient BCAA oxidative metabolism in some tissues. Whether and how impaired BCAA metabolism might occur in obesity is discussed in this Review. Research on the role of individual and model-dependent differences in BCAA metabolism is needed, as several genes (BCKDHA, PPM1K, IVD and KLF15) have been designated as candidate genes for obesity and/or T2DM in humans, and distinct phenotypes of tissue-specific branched chain ketoacid dehydrogenase complex activity have been detected in animal models of obesity and T2DM. Endocrine system and metabolic diseases Nutrition disorders Obesity Type 2 diabetesAssociation between plasma BCAA levels and insulin-resistant obesity in humans, obese Zucker rats, mice with diet-induced obesity (DIO) and ob/ob mice. Data were compiled from elsewhere and redrawn.63, 72, 73, 75 b | Correlation between plasma levels of leucine and fasting levels of HbA1c in African–American women with obesity and T2DM (blue circles) and those with obesity but no T2DM (green circles).
IRS, insulin receptor substrate; mTORC1, mammalian target of rapamycin complex 1; Ra, rate of appearance; Rd, rate of disappearance; S6K1, ribosomal protein S6 kinase β1; T2DM, type 2 diabetes mellitus. The schematic shows how obesity might affect a number of factors contributing to elevated circulating BCAA levels via effects on the Ra or Rd of BCAAs. Loss of steps in BCAA metabolism could lead to the accumulation in tissues of BCKAs and BCAA-related acyl-CoAs. Accumulation of these species in inherited disorders can be mitotoxic and might lead to T2DM and other obesity-related comorbidities. A caveat is that while the metabolites of BCAAs are potentially toxic in maple syrup urine disease and organic acidurias, their role in T2DM-associated mitochondrial dysfunction or in activation of stress kinases is unknown. Alternatively, reduced or incomplete valine and isoleucine catabolism could attenuate anaplerosis from these substrates, contributing to anaplerotic stress in one or more tissues affected by T2DM.
BCKA, branched-chain α-keto acid; BCKDC, branched-chain α-keto acid dehydrogenase complex; FFA, free fatty acid; KLF15, Krueppel-like factor 15; ROS, reactive oxygen species; The genes involved in mitochondrial BCAA metabolism are shown. Note that BCAT(m) activity is essentially absent from the liver. During reversible BCAT(m) metabolism, an intermediate of isoleucine can tautomerize, leading to alloisoleucine formation.182 Alloisoleucine formation increases when BCKDC activity is impaired and might be useful for identifying individuals with impaired BCKDC activity,75 in addition to its usual use in identifying those with maple syrup urine disease. *Indicates an obesity and/or T2DM susceptibility gene.120, 165 ↓ Indicates a literature finding of decreased gene or protein expression observed in human islets or skeletal muscle biopsies from individuals with T2DM, except for HIBADH, which is decreased in skeletal muscle of Goto–Kakizaki rats.154, 155, 165 Coloured oval shapes represent genes implicated in BCAA metabolism.