Insulin resistance and the metabolism of branched-chain amino acids

Abstract

Insulin resistance (IR) is a key pathological feature of metabolic syndrome and subsequently causes serious health problems with an increased risk of several common metabolic disorders. IR related metabolic disturbance is not restricted to carbohydrates but impacts global metabolic network. Branched-chain amino acids (BCAAs), namely valine, leucine and isoleucine, are among the nine essential amino acids, accounting for 35% of the essential amino acids in muscle proteins and 40% of the preformed amino acids required by mammals. The BCAAs are particularly responsive to the inhibitory insulin action on amino acid release by skeletal muscle and their metabolism is profoundly altered in insulin resistant conditions and/or insulin deficiency. Although increased circulating BCAA concentration in insulin resistant conditions has been noted for many years and BCAAs have been reported to be involved in the regulation of glucose homeostasis and body weight, it is only recently that BCAAs are found to be closely associated with IR. This review will focus on the recent findings on BCAAs from both epidemic and mechanistic studies.

Keywords

branched-chain amino acids / leucine / isoleucine / valine / insulin resistance

Introduction

Insulin resistance (IR) is a physiological condition in which target organs including skeletal muscle, adipose tissue and liver fail to respond to the action of insulin effectively. IR causes incomplete suppression of hepatic glucose output and impaired insulin-mediated glucose uptake and utilization in skeletal muscle and adipose tissue, leading to increased insulin requirements. IR and abnormal insulin secretion are two key disorders for the development of type 2 diabetes (T2DM) []. In addition, IR is closely associated with metabolic syndrome [2], which includes central obesity, hyperglycemia, hypertension and dyslipidemia, common risk factors for cardiovascular disease. Obesity is a well-established risk factor for the development of IR [3]. It is estimated that over 200 million men and nearly 300 million women were obese worldwide in 2008 [4]. Obesity-associated resistance to the peripheral action of insulin is a major underlying mechanism causing the metabolic syndrome and ultimately T2DM. IR related metabolic disturbance is widespread, involving not only carbohydrate and fat metabolism, but also protein metabolism [5]. Currently, the mechanisms by which increased fat accumulation leads to IR and metabolic syndrome are not completely understood.

Branched-chain amino acids (BCAAs) include leucine, isoleucine, and valine, which are three of the nine essential amino acids and are relatively abundant in the food supply, accounting for 15%–25% of the total protein intake [6]. In addition to the effects on protein synthesis and degradation, BCAAs were shown to have the capability to improve skeletal muscle glucose uptake and whole body glucose oxidation [7-9]. Cota et al. [10] demonstrated that central administration of leucine decreases food intake and body weight through the activation of mammalian target of rapamycin (mTOR) in hypothalamus. Accordingly, it has been proposed that BCAAs may be responsible for some of the beneficial effects of high-protein diets on body weight and adiposity [6,11,12]. In fact, the elevation of blood levels of amino acids, particularly BCAAs, in insulin resistant states of obesity [13-16] has long been noted for over 40 years. However, BCAAs has never been recognized as a major player in the modulation of insulin action before the study conducted by Newgard et al. [17], in which a BCAA-related metabolic signature showed strongest association with IR. Thereafter, a rapidly growing number of studies linking BCAAs with IR emerged. In this review, we will summarize recent studies about the epidemic associations of BCAAs with IR, possible mechanisms for their elevations in insulin resistant states and the role of BCAAs in insulin signaling.

BCAA metabolism

The first two steps of the pathway in BCAA catabolism by branched-chain aminotransferase (BCAT) and the branched-chain α-keto acid dehydrogenase (BCKDH) complex are common to the three BCAAs [18-21]. BCAT isozymes (including mitochondrial BCAT and cytosolic BCAT) catalyze the transamination of BCAAs, which is the reversible transfer of the α-amino group to α-ketoglutarate. The BCKDH complex, which contains multiple copies of three enzymes, a branched-chain α-keto acid decarboxylase (E1), a dihydrolipoyl transacylase (E2), and a dihydrolipoyl dehydrogenase (E3), catalyzes the oxidative decarboxylation of the branched-chain α-keto acid products of the transamination reaction. Activity of the BCKDH complex is regulated by phosphorylation/dephosphorylation of the E1α subunit [22]. The BCKDH kinase is responsible for inactivation of the complex by phosphorylation of the E1α subunit of the complex [23], and the BCKDH phosphatase is responsible for activation of the complex by dephosphorylation of E1α [24].

In summary, the catabolism of BCAAs, valine, leucine and isoleucine, produces three α-keto acids which are further oxidized by a common branched-chain α-keto acid dehydrogenase, yielding three CoA derivatives. Subsequently, the metabolic pathway diverges, producing intermediates to be used in TCA cycle.

Linkage between BCAAs and IR

In the pioneering study conducted by Newgard et al. [17], application of metabolomics technologies has revealed that BCAAs and related metabolites are more strongly associated with IR than many common lipid species. Principle component analysis (PCA) showed that the component comprising BCAAs, aromatic amino acids and BCAA by-products was most strongly associated with obesity. Importantly, this component was positively related to homeostasis model assessment-insulin resistance (HOMA-IR) index (r = 0.58, P<0.001), an indicator of IR. Furthermore, the authors found that feeding Wistar rats with a high-fat (HF) diet with BCAA (HF/BCAA) reduced food intake and body weight, but caused the animals to be equally insulin resistant compared to heavier rats fed on a non-supplemented HF diet, confirming the contribution of BCAAs to the development of IR. Their findings were further validated in a cross-sectional study [25], in which plasma large neutral amino acids including valine and leucine/isoleucine accounted for most of the variability of IR in 73 overweight/obese individuals without diabetes. Next, the association between BCAAs and IR in normal weight subjects was also found. In a study aimed to investigate the correlates of insulin sensitivity in two groups of healthy individuals, multivariate analysis of the 191 metabolites measured by mass spectrometry revealed that reduction in leucine/isoleucine along with glycerol during oral glucose tolerance test represents the strongest predictor of insulin sensitivity and the decrease of plasma BCAA levels is blunted in insulin-resistant subjects during the oral glucose tolerance test [26]. In 263 non-obese Asian-Indian and Chinese men, Tai et al. [27] found that fatty acids and inflammatory cytokines, which are commonly regarded as IR risk factors, could not discriminate between insulin sensitive and insulin resistant subjects, whereas IR was significantly associated with the increased levels of alanine, proline, valine, leucine/isoleucine, phenylalanine, tyrosine, glutamate/glutamine and ornithine.

In addition to cross-sectional observations, prospective studies demonstrated that the alterations of BCAAs may presage the onset of overt diabetes. A study in the Framingham cohort conducted by Wang et al. [28] reported that baseline BCAAs and aromatic amino acids were significantly associated with future diabetes, and a combination of three amino acids (isoleucine, phenylalanine and tyrosine) could predict incident diabetes 12 years prior to the diagnosis with a more than 5-fold higher risk for individuals in top quartile. More recently, the predictive value of BCAAs has been validated in two large cohorts [29,30]. Besides, baseline BCAA concentrations were positively associated with IR measured 18 months later in healthy children and adolescents [31].

Finally, there is evidence from interventional studies that supports the relationship between BCAAs and IR. In participants from a weight loss trial, Shah et al. [32] demonstrated that the baseline BCAAs and related catabolites were able to predict the improvement of IR, independent of the amount of weight loss. Although it is well known that gastric bypass surgery (GBP) has more beneficial effects on the glycemic control than dietary intervention in patients with morbid obesity and T2DM when assuming an equivalent weight loss, the mechanisms underlying this phenomenon remain elusive. Comparing the circulating amino acids and acylcarnitine profiles between subjects receiving GBP or dietary intervention, Lafferere et al. [33] found that BCAAs were significantly decreased after GBP but not after dietary intervention [33], and BCAAs uniquely correlated with IR, suggesting that the better improvement of glucose homeostasis after GBP could in part be attributed to the changes in BCAAs [28]. Taken together, these studies clearly unveil a BCAA-IR relationship.

As many clinical and experimental measures such as obesity, blood lipids and inflammatory cytokines have been confirmed to be risk factors for insulin resistance, it is natural to ask whether BCAAs are related to these risk factors. However, few studies have addressed this issue to date. Apart form the long-recognized linkage between BCAAs and obesity, Floegel et al. [29] observed that a metabolite factor (in PCA analysis) comprising BCAAs, aromatic amino acids, propionylcarnitine, hexose and diacyl-phosphatidylcholines was positively correlated with triglycerides and liver enzymes. On the other hand, there is emerging evidence that BCAAs associate with insulin resistance and T2DM beyond conventional risk factors. For example, Wang-Sattler et al. [30] reported that BCAAs were predictive for incident T2DM even after adjustment for age, sex, BMI, physical activity, alcohol intake, smoking, systolic blood pressure and HDL cholesterol, suggesting that BCAAs may exert unique effects on insulin resistance and T2DM risk.

Why are BCAAs elevated in IR condition ?

Since BCAAs are essential amino acids, they cannot be synthesized de novo in organisms. Therefore, dietary protein can have a significantly impact on BCAAs in humans. However, the elevation of BCAAs could occur in obesity even after overnight fast [14,15]. In addition, there was no dietary difference between insulin-resistant and-sensitive individuals in either Asia-Indian or Chinese, as investigated by Tai et al. [27]. More specifically, Wang et al. [28] reported comparable intakes of valine, leucine and isoleucine among the study groups of the Framingham cohort, indicating that increased protein consumption is unlikely to be the major driving force behind the abnormally high levels of BCAAs observed in the overweight/obese or insulin resistant subjects. Another potential explanation for the rise in BCAAs could be the accelerated protein degradation, which has been reported in both humans [34] and animal models [35,36] of IR.

Recently, an increasing body of evidence suggests that impaired BCAA catabolism, especially in adipose tissue, contributes to the rise in BCAAs in obesity and insulin resistant states. In two rodent models of obesity (ob/ob mice and Zucker rats), reduced expression of mitochondrial BCAT and the BCKDH complex, which catalyzes the first two enzymatic steps of BCAA catabolism [37], was observed in the adipose tissue of obese mice/rats rather than in lean ones, concordant with significant increase in plasma BCAAs [38]. The authors further examined the expression of BCAT and BCKDH complex in human subjects receiving surgical weight loss intervention (Roux-n-Y gastric bypass) [39]. Significantly decreased BCAAs after surgery together with elevated expression of BCAT and BCKDH complex in oemental and subcutaneous fat were found. Pietiainen et al. [40] performed global gene expression analysis of 14 pairs of monozygotic twins discordant for BMI, finding that BCAA catabolism pathway in adipose tissue was downregulated significantly in obese twins and correlated closely with IR. Via the genetic manipulation of mice, Herman et al. [41] unexpectedly observed that adipose-specific overexpression of GLUT4, an important glucose transporter, resulted in the downregulation of BCAA metabolizing enzymes in the adipose tissue. Interestingly, circulating BCAAs were upregulated accordingly in their report, further supporting an important role of adipose tissue in the modulation of BCAA homeostasis. In a study of Zucker rats treated with one of the four peroxisome proliferator-activated receptor γ (PPARγ) ligands including thiazolidinedione (TZD), BCAA catabolic pathway in the adipose tissue significantly correlated with ligand treatment-specific insulin-sensitizing potency [42]. Treating human subjects with TZDs produced similar results [43]. While most aberrations of BCAA metabolism in obesity and insulin resistant states were found in adipose tissue, Lefort et al. [44] reported lower BCAA metabolizing enzymes (methyl-malonate-semialdehyde dehydrogenase and propionyl-CoA carboxylase β) in mitochondria isolated from skeletal muscle of the obese group. However, blood BCAA levels were not measured, precluding the possibility to evaluate the role of skeletal muscle in the modulation of circulating BCAAs. These studies suggest that the decreased catabolism of BCAA in adipose tissue and possibly skeletal muscle may in part be responsible for the higher levels of BCAAs in insulin resistant states including obesity.

The possible mechanisms underlying altered BCAAs in IR

The mTOR is a serine/threonine kinase that belongs to the phosphatidylinositol (PI) kinase-related protein kinase family [45]. The mTOR protein is mainly known for its role in regulating cell growth, notably via protein synthesis. However, during recent years, mTOR has been considered as the central signaling molecule mediating the crosstalk between amino acids and insulin. Stimulation of mTOR activates p70 ribosomal S6 kinase (p70S6K), a key mediator of the protein synthesis cascade [46] and subsequently leads to the phosphorylation of its downstream target, ribosomal protein S6 kinase (S6K). This results in the translation of mRNAs which encode for ribosomes and transcription factors. Moreover, activation of S6K1 leads to serine/threonine phosphorylation and therefore the inhibition of insulin receptor substrate (IRS)-1, not only interfering with the normal insulin signaling, but also causing the proteosomal degradation of IRS-1 [47-50].

Leucine stimulates IRS-1 Ser-636/639 phosphorylation in a rapamycin-sensitive manner in both 3T3-L1 adipocytes and L6 myotubes in vitro [51]. BCAA supplementation was shown to increase the activation of mTOR and subsequent S6K1 phosphorylation, coupled with IRS-1 Ser-307 phosphorylation in the skeletal muscle of rats [17]. Likewise, Tremblay et al. [52] reported increased phosphorylation of the IRS-1 Ser-1011 via mTOR/p70S6K/S6K1 pathway and decreased insulin-induced phosphoinositide 3-kinase (PI3K) activity, which is critical for insulin signaling, in human skeletal muscle under amino acid infusion.

In addition to the well-established mTOR/p70S6K/S6K1 pathway, it has been shown that leucine deprivation significantly increased the activation of MAP-activated protein kinase (AMPK) both in the livers of mice and in HepG2 cells as compared with controls [53]. The downregulation of AMPK decreased insulin-stimulated phosphorylation of insulin receptor and protein kinase B (AKT), indicative of impaired insulin signaling. General control nonderepressible (GCN) 2 is a sensor of amino acid deprivation that triggers a repression of global protein synthesis while simultaneously inducing translation of specific proteins [54,55]. In the same study mention above, Xiao et al. [53] revealed that leucine deprivation was associated with increased phosphorylation of GCN2 and concurrent improvement of insulin sensitivity. Intriguingly, GCN2 acted as an upstream inhibitor of mTOR as evidenced by the inability of leucine deprivation to blunt mTOR activation in Gcn2^-/- mice. Moreover, Guo et al. [56] found that the expression of SREBP-1c, a key transcriptional activator of the de novo lipogenic pathway, was significantly downregulated in a GCN2-dependent manner in livers of mice fed a leucine-deficient diet, accompanied by diminished levels of several lipogenic enzymes and a dramatic loss of abdominal adipose mass. This phenomenon implies that, insulin signaling aside, BCAAs could impact on lipid metabolism and subsequently exert an indirect effect on insulin sensitivity.

It needs to be pointed out that an extensive review of previous studies presents a more complex picture regarding the role of BCAAs in the modulation of insulin sensitivity. For instance, Macotela et al. [57] reported that doubling dietary leucine in mice under high fat diet (HFD) caused marked improvement in glucose tolerance, decreased hepatic steatosis and decreased inflammation in adipose tissue despite the enhanced activation of mTOR/p70S6K pathway, suggesting that leucine may modify multiple signaling pathways in multiple tissue, the precise mechanisms of which remain largely unknown.

Conclusions and future perspectives

The research on BCAAs and IR presents a general picture of the BCAAs-IR relationship (Fig. 1): (1) the expression of genes related to BCAA catabolism was downregulated in adipose tissue and possibly skeletal muscle, leading to BCAA accumulations, although the mechanisms were not fully understood; (2) The elevated BCAAs could then activate the mTOR/p70S6K, AMPK and GCN2 pathways, thereby contributing to the development of IR.

However, it is noteworthy that some conflicting results have been reported concerning the role of BCAAs in the regulation of IR. For instance, using a genetic mouse model, She et al. [38] reported that the elevation of BCAAs was accompanied with increased energy expenditure and better insulin sensitivity. Nishitani et al. [9] reported that leucine and isoleucine improved glucose metabolism by promoting glucose uptake in skeletal muscle in rats with liver cirrhosis. Leucine supplementation was shown to significantly improve glucose intolerance and insulin resistance caused by HFD [57] and similarly, leucine supplementation via drinking water prevented HFD-induced obesity and hyperglycemia [58], while no effect of leucine supplementation on the HFD-induced obesity was observed by Nairizi et al. [59]. Given that most studies favoring a beneficial effect of BCAAs on IR were based on dietary supplementation, one possible explanation for the discrepancies could be that BCAAs are not direct contributors to IR and that its elevation could simply be a marker of the biological perturbations driving the development of IR, which merits further investigation. It is also interesting to note that these studies were conducted in animal models while recent population-based human studies with large sample size indicated that the increase of BCAAs is an early event of T2DM, raising the possibility that the effects of BCAAs on IR may be species-specific.

In conclusion, recent studies suggest a close relationship between BCAAs and IR and demonstrate that BCAAs may play a major role in the modulation of insulin action, despite some inconsistent results reported from different laboratories. Progress in this field will definitely deepen our understanding in insulin resistant states such as obesity, metabolic syndrome and T2DM. In addition, BCAA metabolic pathways may also serve as potential targets for the treatment of metabolic disorders.

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