A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance
Open accessAbstract
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 a low rate of weight gain equivalent to the SC group, HF/BCAA rats were as 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 IRS1Ser307 and by accumulation of multiple acylcarnitines in muscle, and it was reversed by the mTOR inhibitor, rapamycin. Our findings show that in the context of a dietary pattern that includes high fat consumption, BCAA contributes to development of obesity-associated insulin resistance.
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Recent metabolomic studies in humans and BCAA/high-fat feeding studies in rodents indicate that alterations in BCAA metabolism are associated with insulin resistance.
“Moreover, recent metabolomic studies in humans and BCAA/high-fat feeding studies in rodents indicate that alterations in BCAA metabolism are associated with insulin resistance (49,50).”
Feeding rats a diet enriched with fat and branched-chain amino acids causes insulin resistance together with elevated intramuscular even- and odd-chain acylcarnitines.
“feeding rats a diet enriched with both fat and branched chain amino acids caused insulin resistance in association with elevated intramuscular levels of both even and odd chain acylcarnitine metabolites [64].”
From Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused? (2010) · cites this paper as [64]
Human studies report increased plasma acylcarnitine levels in association with insulin resistance and diabetes.
“Human studies have also reported increased plasma acylcarnitine levels in association with insulin resistance and diabetes [1,37,52,64].”
From Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused? (2010) · cites this paper as [64]
Recent cross-sectional studies have documented differences in blood metabolite profiles before and after glucose loading and between obese and lean individuals.
“Recent cross-sectional studies have documented differences in blood metabolite profiles before and after glucose loading15-17 and in obese compared with lean individuals14.”
From Metabolite profiles and the risk of developing diabetes (2011) · cites this paper as [14]
Studies of branched-chain amino acid supplementation in animals and humans indicate that circulating amino acids may directly promote insulin resistance, possibly by disrupting insulin signaling in skeletal muscle.
“Studies of branched chain amino acid supplementation in both animals14 and humans22 indicate that circulating amino acids may directly promote insulin resistance, possibly via disruption of insulin signaling in skeletal muscle.”
From Metabolite profiles and the risk of developing diabetes (2011) · cites this paper as [14]
Experimental and clinical data suggest that certain amino acids may be both markers and effectors of insulin resistance.
“Our findings, which highlight five branched chain and aromatic amino acids from 61 metabolites profiled, are particularly noteworthy in the context of experimental and clinical data suggesting that certain amino acids may be both markers and effectors of insulin resistance14,15,18,20,21.”
From Metabolite profiles and the risk of developing diabetes (2011) · cites this paper as [14]
The rise of BCAA has been associated with insulin resistance.
“the rise of BCAA has been associated with insulin resistance [107]”
From The athletic gut microbiota (2020) · cites this paper as [107]
BCAAs have recently been demonstrated to accumulate in the context of obesity and insulin resistance.
“BCAAs have recently been demonstrated to accumulate in the context of obesity and insulin resistance (Adams, 2011; Newgard et al., 2009; Wang et al., 2011), though the mechanisms leading to this metabolic phenotype (i.e., higher intake, decreased catabolism) are not yet clear.”
From Regulation of Substrate Utilization by the Mitochondrial Pyruvate Carrier (2014) · cites this paper as Newgard et al., 2009
Mpc inhibition may potentiate oxidation of BCAAs or other amino acids that accumulate in the context of insulin resistance.
“Mpc inhibition may potentiate oxidation of BCAAs or other amino acids that accumulate in the context of insulin resistance (Adams, 2011; Newgard et al., 2009; Wang et al., 2011).”
From Regulation of Substrate Utilization by the Mitochondrial Pyruvate Carrier (2014) · cites this paper as Newgard et al., 2009
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- Authors
- Newgard, C. B., An, J., Bain, J. R., Muehlbauer, M. J., Stevens, R. D., Lien, L. F., Haqq, A. M., Shah, S. H., Arlotto, M., Slentz, C. A., Rochon, J., Gallup, D., Ilkayeva, O., Wenner, B. R., Yancy, W. S., Eisenson, H., Musante, G., Surwit, R. S., Millington, D. S., Butler, M. D., & Svetkey, L. P.
- Affiliations
- Duke University (US)
- Duke Medical Center (US)
- Corresponding author
- Newgard, Christopher B.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2009-04
- Volume
- 9
- Issue
- 4
- Pages
- 311-326
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3640280
- OpenAlex
- W2122367003
- Cited by
- 3,165
- References
- 61
- Citations by year
- 2026: 173 · 2025: 186 · 2024: 199 · 2023: 220 · 2022: 250 · 2021: 297 · 2020: 249 · 2019: 208 · 2018: 257 · 2017: 177 · 2016: 201 · 2015: 153 · 2014: 167 · 2013: 153 · 2012: 130
- FWCI
- 66.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5k23rr021979-02)
- National Heart, Lung, and Blood Institute (U01HL068734)
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK058398)
- National Center for Research Resources (1K23-RR-021979, K23-RR-021979)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- branched-chain amino acids, insulin resistance, obesity, high-fat diet, metabolomic signatures, acylcarnitines, mTOR signaling, JNK phosphorylation, rapamycin, muscle, pair feeding, dietary supplementation
- MeSH terms
- Amino Acids, Branched-Chain, Animals, Demography, Dietary Fats, Feeding Behavior, Female, Hormones, Humans, Insulin, Insulin Resistance, Male, Middle Aged, Obesity, Mass Spectrometry, Thinness, Signal Transduction, Cytokines, Rats, Wistar, Dietary Supplements, Rats, Metabolomics, Metabolome
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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