Branched-chain amino acids in metabolic signalling and insulin resistance

Abstract

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.

Conflict of interest statement

Competing interests

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.

Figures

Figure 1

Plasma BCAA levels and insulin-resistant obesity. a | Association 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.,,,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). Abbreviations: BCAA, branched-chain amino acid; IR, insulin resistant; T2DM, type 2 diabetes mellitus. Adapted from Fiehn, O. et al. PLoS ONE 5, e15234 (2010), which is published under a Creative Commons Licence owned by PLOS ©.

Figure 2

Persistent activation of mTORC1 links increased plasma BCAA levels to insulin resistance. According to this theory,,, excess nutrients that lead to obesity also result in frequent prandial increases in plasma levels of leucine, which together with insulin activate mTORC1 and S6K1. Persistent activation leads to serine phosphorylation of IRS-1 and IRS-2, which interferes with signalling and might target IRS1 for proteolysis via a proteasomal pathway., The resulting insulin resistance increases demand on insulin to dispose of excess glucose. Insulin resistance might increase the Ra of BCAAs from protein degradation. Long-term demand for insulin secretion, along with other factors such as lipotoxicity, might negatively affect the function of islets (for example, an initial compensatory increase in β-cell numbers and mass and islet mass, followed by apoptosis), ultimately resulting in a failure to produce sufficient quantities of insulin and leading to the onset of T2DM. Abbreviations: BCAA, branched-chain amino acid; 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.

Figure 3

BCAA dysmetabolism links elevated plasma levels of BCAAs and FFAs to T2DM and obesity-related comorbidities. 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. Abbreviations: BCAA, branched-chain amino acid; BCKA, branched-chain α-keto acid; BCKDC, branched-chain α-keto acid dehydrogenase complex; CoA, coenzyme A; FFA, free fatty acid; KLF15, Krueppel-like factor 15; Ra, rate of appearance; Rd, rate of disappearance; ROS, reactive oxygen species; T2DM, type 2 diabetes mellitus.

Figure 4

Mitochondrial genes attributed to BCAA metabolism. 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. Alloisoleucine formation increases when BCKDC activity is impaired and might be useful for identifying individuals with impaired BCKDC activity, in addition to its usual use in identifying those with maple syrup urine disease. *Indicates an obesity and/or T2DM susceptibility gene., ↓ 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.,, Coloured oval shapes represent genes implicated in BCAA metabolism. Abbreviations: BCAA, branched-chain amino acid; BCAT(m), branched-chain-amino-acid aminotransferase, mitochondrial; BCKDC, branched-chain α-ketoacid dehydrogenase complex; KIC, α-ketoisocaproate; KIV, 2-ketoisovalerate; KMV, α-keto-β-methylvalerate. Modified with permission from Herman, M. A. et al. J. Biol. Chem. 285, 11348–11356 (2010) © The American Society for Biochemistry and Molecular Biology.

Figure 5

Patterns of altered BCAA metabolism observed in animal models of obesity. Losses of adipose tissue BCAA metabolic gene and protein expression in obesity have consistently been observed. In a rat model of diet-induced obesity, reduced levels of BCAA metabolizing enzymes in adipose tissue seem to be compensated for by increased hepatic BCKDH activity (termed a type B response). In contradistinction, hepatic BCKDH was also attenuated in other models such as ZDF rats,, Zucker fa/fa rats,, ob/ob mice and Otsuka Long–Evans Tokushima Fatty rats (termed a type A response). Multiple peripheral tissues were examined and found to be affected in Zucker rats. These distinct phenotypes are important because uncompensated loss of BCAA metabolism in multiple peripheral tissues could result in a higher range of plasma BCAAs that, when observed in states of obesity, associate to a greater extent with insulin resistance, levels of glycaemia and future T2DM. Alloisoleucine elevations below the level used to screen for MSUD have been proposed as a strategy to distinguish between these phenotypes. Levels of BCAAs were considerably increased in models in which metabolism was impaired (↑↑). Abbreviations: BCAA, branched-chain amino acid; BCKDH, branched-chain α-keto acid dehydrogenase; MSUD, maple syrup urine disease. Adapted with permission from John Wiley and Sons © Olson, K. C. et al. Obesity (Silver Spring) 22, 1212–1215 (2014).