Branched-chain amino acids in disease

White, Phillip J.; Newgard, Christopher B.

doi:10.1126/science.aav0558

Cited by 205 publications

(167 citation statements)

References 16 publications

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“…Among the candidate proteins with the strongest support, we found HIBCH that is a BCAA catabolic enzyme, where the MR estimate suggested an inverse causal effect between the proteins and risk of T2DM. Circulating BCAAs levels have consistently been shown to predict T2DM 27 although the underlying mechanisms are complex and remain to be fully understood 28 . Our findings support a model where higher protein expression of the BCAA catabolic pathway reduces risk of T2DM.…”

Section: Discussionmentioning

confidence: 99%

Deep serum proteomics reveal biomarkers and causal candidates for type 2 diabetes

Guðmundsdóttir

Emilsson

Aspelund

et al. 2019

Preprint

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18The prevalence of type 2 diabetes mellitus (T2DM) is expected to increase rapidly in the next 19 decades, posing a major challenge to societies worldwide. The emerging era of precision 20 medicine calls for the discovery of biomarkers of clinical value for prediction of disease 21 onset, where causal biomarkers can furthermore provide actionable targets. Blood-based 22 factors like serum proteins are in contact with every organ in the body to mediate global 23 homeostasis and may thus directly regulate complex processes such as aging and the 24 development of common chronic diseases. We applied a data-driven proteomics approach 25 measuring serum levels of 4,137 proteins in 5,438 Icelanders to discover novel biomarkers for 26 incident T2DM and describe the serum protein profile of prevalent T2DM. We identified 536 27 proteins associated with incident or prevalent T2DM. Through LASSO penalized logistic 28 regression analysis combined with bootstrap resampling, a panel of 20 protein biomarkers that 29 accurately predicted incident T2DM was identified with a significant incremental 30 improvement over traditional risk factors. Finally, a Mendelian randomization analysis 31 provided support for a causal role of 48 proteins in the development of T2DM, which could 32 be of particular interest as novel therapeutic targets. 33 34 for age and sex, we identified 520 unique proteins that were significantly associated with 84 prevalent T2DM after Bonferroni correction for multiple hypothesis testing (P adj < 0.05), with 85 the strongest associations observed for ARFIP2, MXRA8 and CPM ( Fig. 1a, Table S2). In a 86 second model including adjustment for body mass index (BMI), 322 proteins remained 87 statistically significant ( Table S2). Many of the proteins were inter-correlated, with pairwise 88 Pearson's r ranging from -0.60 to 0.97 ( Fig. S2a). A pathway and gene ontology (GO) 89 enrichment analysis of all 520 proteins associated with prevalent T2DM revealed an 90 enrichment of proteins involved in extracellular matrix (ECM)-receptor interaction, 91 complement and coagulation cascades, metabolic processes and extracellular region (Fig. 92 S3a, Table S3). We furthermore found the genes encoding the 520 prevalent T2DM-93 associated proteins to be enriched for high expression in liver, followed by other tissues that 94 included kidney, gastrointestinal tract and pancreas ( Fig. S4a). Thus, the diabetic state is 95 reflected in a major shift in the serum proteome that is involved in metabolic, inflammatory 96 and ECM processes. 97 98 Serum protein profile of incident T2DM 99The serum protein profiles of T2DM patients observed in the cross-sectional analysis 100 described above may represent shifts that occurred either before or after the onset of the 101 disease. To identify serum protein signatures that preceded the onset of T2DM, we next 102 focused our analysis on the 2,940 non-diabetic AGES participants who participated in a 103 second study visit (AGESII) 5-years after the baseline visit, of which 112 develop...

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Section: Discussionmentioning

confidence: 99%

Deep serum proteomics reveal biomarkers and causal candidates for type 2 diabetes

Guðmundsdóttir

Emilsson

Aspelund

et al. 2019

Preprint

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“…A potential explanation for the discord between findings to date is the challenge associated with studying the impact of amino acids on tissue metabolism in vivo. As noted by others (White and Newgard 2019), supplementing with individual amino acids or manipulating systemic mTORc1 function also impacts metabolism in distal tissues, potentially underpinning the inconsistent observations seen between studies. Thus, to circumvent these issues, the aim of the current study was to delineate the role of leucine on glucose uptake in cultured muscle cells, utilizing multiple strategies to manipulate leucine availability and mTORc1 function so as to ascertain their contribution to insulin-stimulated glucose uptake.…”

Section: Introductionmentioning

confidence: 95%

Leucine and mTORc1 act independently to regulate 2-deoxyglucose uptake in L6 myotubes

et al. 2020

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Chronic mTORc1 hyperactivation via obesity-induced hyperleucinaemia has been implicated in the development of insulin resistance, yet the direct impact of leucine on insulin-stimulated glucose uptake in muscle cells remains unclear. To address this, differentiated L6 myotubes were subjected to various compounds designed to either inhibit mTORc1 activity (rapamycin), blunt leucine intracellular import (BCH), or activate mTORc1 signalling (3BDO), prior to the determination of the uptake of the glucose analogue, 2-deoxyglucose (2-DG), in response to 1 mM insulin. In separate experiments, L6 myotubes were subject to various media concentrations of leucine (0-0.8 mM) for 24 h before 2-DG uptake in response to insulin was assessed. Both rapamycin and BCH blunted 2-DG uptake, irrespective of insulin administration, and this occurred in parallel with a decline in mTOR, 4E-BP1, and p70S6K phosphorylation status, but little effect on AKT phosphorylation. In contrast, reducing leucine media concentrations suppressed 2-DG uptake, both under insulin-and non-insulin-stimulated conditions, but did not alter the phosphorylation state of AKT-mTORc1 components examined. Unexpectedly, 3BDO failed to stimulate mTORc1 signalling, but, nonetheless, caused a significant increase in 2-DG uptake under non-insulin-stimulated conditions. Both leucine and mTORc1 influence glucose uptake in muscle cells independent of insulin administration, and this likely occurs via distinct but overlapping mechanisms.

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“…Lack of Pp2cm only partially impairs BCAA catabolism but does result in increased levels of circulating BCAAs (34). Overexpression of Ppm1k (gene coding for Pp2cm) lowers circulating BCAA levels, reduces hepatic steatosis and improves glucose tolerance in the absence of weight loss in Zucker fatty rats (16,48). We also chose to use a total body knock out model, instead of adipocyte-specific knock out, to prevent a compensatory shift of increased BCAA catabolism by other tissues.…”

Section: Discussionmentioning

confidence: 99%

“…These findings consistently demonstrate that perturbations in BCAA homeostasis are associated with metabolic dysfunction. The mechanisms behind these observations have been posited in several recent reviews on this topic (13)(14)(15)(16). Importantly, these data have led to the hypothesis that increased BCAA levels directly contribute to metabolic dysfunction in obese and diabetic patients.…”

Section: Introductionmentioning

confidence: 99%

The role of elevated branched chain amino acids in the potent effects of vertical sleeve gastrectomy to reduce weight and improve glucose regulation in mice

Bozadjieva-Kramer

Evers

Shin

et al. 2020

Preprint

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Obesity and type 2 diabetes mellitus (T2D) are growing epidemics resulting in increased morbidity and mortality. An emerging body of evidence has shown that elevated levels of branched-chain amino acids (BCAA) and their metabolites are strongly positively associated with obesity, insulin-resistance and T2D. Bariatric surgery is among the best treatments for weight loss and the alleviation of T2D. Additionally, clinical studies have reported that bariatric surgery decreases the circulating levels of BCAA. The objective of these studies was to test the hypothesis that reduced BCAA levels contribute to the metabolic improvements after VSG. We find that, as in humans, circulating BCAA levels are significantly lower in VSG rats and mice compared to Sham controls. In order to increase circulating BCAA levels, we tested mice with either increased dietary intake of BCAA or impaired BCAA catabolism by total body deletion of mitochondrial phosphatase 2C, Pp2cm, a key enzyme in the rate-limiting step in BCAA catabolism. Our results show that a decrease in circulating BCAA levels is not necessary for sustained body weight loss and improved glucose tolerance after VSG. While it is clear that circulating levels of BCAAs are excellent biomarkers for metabolic status, the current data do not support a causal role in determining metabolic regulation and the response to VSG.

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Branched-chain amino acids in disease

Abstract: Are BCAAs a biomarker, causal agent, or both in cardiometabolic disease?

Cited by 205 publications

References 16 publications

Deep serum proteomics reveal biomarkers and causal candidates for type 2 diabetes

Deep serum proteomics reveal biomarkers and causal candidates for type 2 diabetes

Leucine and mTORc1 act independently to regulate 2-deoxyglucose uptake in L6 myotubes

The role of elevated branched chain amino acids in the potent effects of vertical sleeve gastrectomy to reduce weight and improve glucose regulation in mice

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