A Branched-Chain Amino Acid-Related Metabolic Signature that Differentiates Obese and Lean Humans and Contributes to Insulin Resistance

By Christopher B. Newgard, J. An, J. Bain, M. Muehlbauer, R. Stevens, Lillian F. Lien, Andrea M. Haqq, Svati H. Shah, M. Arlotto, C. Slentz and 11 more. Cell Metabolism, 2009

3,058 citations recorded by the source corpus.

Summary Metabolomic profiling of obese versus lean humans reveals a branched-chain amino acid (BCAA)-related metabolite signature that is suggestive of increased catabolism of BCAA and correlated with insulin resistance. To test its impact on metabolic homeostasis, we fed rats on high-fat (HF), HF with supplemented BCAA (HF/BCAA) or standard chow (SC) diets. Despite having reduced food intake and weight gain equivalent to the SC group, HF/BCAA rats were equally insulin resistant as HF rats. Pair-feeding of HF diet to match the HF/BCAA animals or BCAA addition to SC diet did not cause insulin resistance. Insulin resistance induced by HF/BCAA feeding was accompanied by chronic phosphorylation of mTOR, JNK, and IRS1(ser307), accumulation of multiple acylcarnitines in muscle, and was reversed by the mTOR inhibitor, rapamycin. Our findings show that in the context of a poor dietary pattern that includes high fat consumption, BCAA contributes to development of obesity-associated insulin resistance.

View Paper: https://www.semanticscholar.org/paper/4e54cf73732c73c4a854ef693fe576d9e842e6b7

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

M. Guasch-Ferré
F. B. Hu
A. Hruby
M. Schulze
Efsa Panel on Dietetic Products
K. Copps
Kıvanç Birsoy
M. Martínez-González

Citations in the corpus

Cultured gut microbiota from twins discordant for obesity modulate adiposity and metabolic phenotypes in mice (2013, unknown): “These specific amino acids, as well as the magnitude of their differences, are remarkably similar to elevations in BCAA and related amino acids reported in obese and insulin-resistant versus lean and insulinsensitive humans (25).”
Metabolomics in Prediabetes and Diabetes: A Systematic Review and Meta-analysis (2016, background): “(19) where BCAAs, aromatic amino acids, and glutamate-to-glutamine ratio were positively associated with prediabetes in obese individuals.”
α-Hydroxybutyrate Is an Early Biomarker of Insulin Resistance and Glucose Intolerance in a Nondiabetic Population (2010, methodology): “aromatic amino acids (phenylalanine and tyrosine) using principal component analysis [36].”
An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis (2015, background): “As blood aspartate concentrations in children and adults are very low (0–15 uM) (Newgard et al., 2009; Wuu et al., 1988), it is unlikely that in vivo cells with ETC inhibition can take”
Scientific Opinion on Dietary Reference Values for protein. (2012, background): “Some studies using metabolomic profiling in humans also suggested a BCAA-related metabolite signature that could be correlated with insulin resistance in obese subjects (Newgard et al., 2009) or with future diabetes (Wang et al.”
Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements (2018, background): “The studies have shown that the BCAA levels in obesity correlate with insulin resistance and are a sensitive predictor of diabetes in the future [78, 79].”
Autophagy in the Cellular Energetic Balance (2011, unknown): “Additional mechanisms such as the chronic upregulation of mTOR signaling observed in obesity (Newgard et al., 2009) may contribute to decreased macroautophagy.”
Branched Chain Amino Acids: Beyond Nutrition Metabolism (2018, background): “The results from a previous study have suggested that increased BCAAs catabolic flux may contribute to increased gluconeogenesis and glucose intolerance via glutamate transamination to alanine [3].”
Increased Levels of Plasma Acylcarnitines in Obesity and Type 2 Diabetes and Identification of a Marker of Glucolipotoxicity (2010, unknown): “Two recent human studies comparing AcylCN patterns in lean and obese (21) or obese individuals with or without T2DM (22) observed some of the same patterns we observed in this study.”