Branched-chain amino acids in metabolic signalling and insulin resistance

By C. Lynch, S. Adams. Nature Reviews Endocrinology, 2014

1,302 citations recorded by the source corpus.

Branched-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.

Subfields: Biochemistry, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/f364004b0a6736dc98c7a546c1d27688c41fa4a7

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In Biochemistry

1. Joshua D. Rabinowitz
2. Luigi Fontana
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In Molecular Biology

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2. Li Chen
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Citations in the corpus

• Health Benefits of the Mediterranean Diet: Metabolic and Molecular Mechanisms (2018, positive): “Interestingly, accumulating data indicate that the branched-chain amino acids, leucine, isoleucine, and valine, play a key role in modulating insulin sensitivity (81).”
• Branched Chain Amino Acids: Beyond Nutrition Metabolism (2018, background): “However, the relationship between BCAAs and T2DM inducing deterioration of pressure overloaded heart disease remains controversial.”
• Metabolomics and isotope tracing (2018, background): “Indeed, elevated BCAAs were found early in standard mouse diabetes models (Lynch and Adams, 2014).”