Branched-chain amino acids (BCAAs) have beneficial nutrient signalling effects but paradoxically are associated with obesity, insulin resistance and type 2 diabetes mellitus (T2DM)
BCAAs might be a marker of, rather than, a cause of insulin resistance, as insulin resistance increases the rate of appearance of BCAAs and is linked to reduced expression of mitochondrial BCAA catabolic enzymes
Alternatively, two mechanisms have emerged indicating that a causative link exists between increased plasma concentrations of BCAAs and T2DM or insulin resistance
In the first mechanism, persistent activation of the mammalian target of rapamycin complex 1 signalling pathway uncouples the insulin receptor from the insulin signalling mediator, IRS-1, which leads to insulin resistance
In the second mechanism, abnormal BCAA metabolism in obesity results in accumulation of toxic BCAA metabolites that in turn trigger the mitochondrial dysfunction and stress signalling associated with insulin resistance and T2DM
Factors that alter expression of genes involved in the BCAA metabolic pathway (or post-translational modification of the encoded proteins) are associated with obesity and T2DM; three genes in the pathway are candidate genes for obesity and/or T2DM
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.
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C.J.L. acknowledges research support from the NIH (DK091784 and DK084428). S.H.A. acknowledges research support from the USDA–Agricultural Research Service (Intramural Project 5,306-51530-019-00) and the NIH (NIH-NIDDK R01DK078328). The authors wish to thank their many colleagues, collaborators and mentors who have inspired their interest in branched-chain amino acids and metabolic disease.
C.J.L. has received an honorarium for being a panelist for the Protein Summit, Washington, DC, USA, in 2013. S.H.A. declares no competing interests.
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Lynch, C., Adams, S. Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol 10, 723–736 (2014). https://doi.org/10.1038/nrendo.2014.171
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