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β-Aminoisobutyric Acid Induces Browning of White Fat and Hepatic β-Oxidation and Is Inversely Correlated with Cardiometabolic Risk Factors
Open accessAbstract
The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) regulates metabolic genes in skeletal muscle and contributes to the response of muscle to exercise. Muscle PGC-1α transgenic expression and exercise both increase the expression of thermogenic genes within white adipose. How the PGC-1α-mediated response to exercise in muscle conveys signals to other tissues remains incompletely defined. We employed a metabolomic approach to examine metabolites secreted from myocytes with forced expression of PGC-1α, and identified β-aminoisobutyric acid (BAIBA) as a small molecule myokine. BAIBA increases the expression of brown adipocyte-specific genes in white adipocytes and β-oxidation in hepatocytes both in vitro and in vivo through a PPARα-mediated mechanism, induces a brown adipose-like phenotype in human pluripotent stem cells, and improves glucose homeostasis in mice. In humans, plasma BAIBA concentrations are increased with exercise and inversely associated with metabolic risk factors. BAIBA may thus contribute to exercise-induced protection from metabolic diseases.
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“β-aminoisobutyric acid (BAIBA) are natural metabolites of thymine and valine secreted primarily by myocytes during the practice of physical exercise (Roberts et al., 2014).”
From Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases (2018) · cites this paper as Roberts et al., 2014
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The increase of PGC1α observed during physical exercise results in a concomitant increase in BAIBA serum levels.”
From Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases (2018) · cites this paper as Roberts et al., 2014
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“For example, β‐aminoisobutyric acid (BAIBA), a novel exercise‐induced muscle factor, attenuates insulin resistance, improves glucose tolerance, and promotes the browning of white adipose tissue (WAT) and hepatic β‐oxidation (Roberts et al, 2014; Jung et al, 2015).”
From Exercise‐induced α‐ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1‐dependent adrenal activation (2020) · cites this paper as Roberts et al, 2014
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“two studies have reported increased circulating levels of BAIBA following aerobic exercise, e.g., cycling for 1 h at 40% maximal power output [106] or after 20 weeks of 30–50 min cycling sessions at 55–75% VO2 max [104] in healthy young men.”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [104]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The myokines irisin [57] and BAIBA [104] have been described to directly induce WAT “browning” both in vitro and in vivo, by upregulating genes involved in mitochondrial biogenesis, FAO, oxidative phosphorylation, and thermogenesis (1).”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [104]
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“Fat mass loss associated with increased total energy expenditure was also observed [104].”
The cited source says what the claim attributes to it.
In the citing paper
“A trend toward a negative correlation between BAIBA and BMI [104] was shown, while another study reported no increase [107].”
The cited source says what the claim attributes to it.
In the citing paper
“which is known to upregulate the WAT browning myokines FNDC5-irisin [57], METRNL [274], and BAIBA [104].”
The cited source says what the claim attributes to it.
In the citing paper
“For instance, BAIBA [104] and FGF21 [160] have been shown to increase hepatic β-oxidation (6)”
The cited source says what the claim attributes to it.
In the citing paper
“in addition to demonstrating that physical exercise increases its production by the body.”
From Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases (2018) · cites this paper as Roberts et al., 2014
The cited source says what the claim attributes to it.
In the citing paper
“In the same study, in vitro, when BAIBA was cultivated with primary cells from subcutaneous adipose tissue (scAT), there was an up regulation of brown and beige adipocytes marker, such as UCP1 and CIDEA.”
From Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases (2018) · cites this paper as Roberts et al., 2014
In the citing paper
“Thus, whether exercise can brown WAT in humans, especially through an irisin-mediated pathway, remains controversial55,83,84,90.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [55]
In the citing paper
“In humans, circulating levels of β-aminoisobutyric acid (BAIBA) increased with chronic training55 and inversely correlated with insulin resistance55.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [55]
In the citing paper
“In wild-type mice, BAIBA treatment reduced insulin resistance and suppressed inflammation55.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [55]
In the citing paper
“Using a mouse model, this paper demonstrated that a myokine, BAIBA, can ‘brown’ WAT to improve glucose homeostasis.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [55]
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“BAIBA is a catabolite of thymine and valine metabolism that has been shown to be inversely associated with cardiometabolic risk, released from muscle in response to exercise and PGC- 1alpha overexpression, induces adipose browning, and improves glucose metabolism (Roberts et al., 2014).”
BackgroundCirculating molecules that control brown/beige adipocyte differentiation and thermogenic capacity
Ludwig, R. G., Rocha, A. L. S., & Mori, M. A. (2018) · Cell Biology International · doi:10.1002/cbin.10946 · Cited by 6
“The b-Aminoisobutyric Acid (BAIBA) is a metabolite that is up-regulated during physical activity (Roberts et al., 2014).”
BackgroundInfluentialExerkines: Benign adaptation for exercise and benefits for non-alcoholic fatty liver disease
Chen, Y., Zhang, Y., Jin, X., Hong, S., & Tian, H. (2024) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2024.150305 · Cited by 5
Chen, L.-S., & Liu, L. (2024) · Clinical Nutrition · doi:10.1016/j.clnu.2024.07.024 · Cited by 5
Exercise as elixir to combat cardiovascular ageing
Feng, Z., Yuan, X., Yi, W., Gao, F., Sun, Y., & Zhang, X. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102848 · Cited by 7
Vallejo, J. A., Kitase, Y., Thiagarajan, G., Dallas, M., Xie, Y., Moore, D. S., Johnson, M. L., Bonewald, L. F., & Wacker, M. (2025) · Aging · doi:10.18632/aging.206325 · Cited by 5
“BAIBA promotes the browning of white adipose tissue through PPAR α [22].”
InfluentialThe role of brown adipose tissue in mediating healthful longevity
Zhang, J., Kibret, B. G., Vatner, D. E., & Vatner, S. F. (2024) · The Journal of Cardiovascular Aging · doi:10.20517/jca.2024.01 · Cited by 6
“Physical exercise copes with increased levels of specific molecules, including β -aminoisobutyric acid and irisin, which induce adipose tissue browning [44,45] .”
BackgroundTu, C., Chen, Y.-B., Lai, S.-Q., Yu, Y.-P., Huang, Z., Li, H.-Z., Ao, R.-F., Han, D. C., Gao, J.-W., Zhu, G.-Z., et al. (2024) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2024.167269 · Cited by 6
Blümlhuber, A., Freuer, D., Wawro, N., Rohm, F., Meisinger, C., & Linseisen, J. (2025) · Metabolites · doi:10.3390/metabo15070441 · Cited by 5
“…and amino acid metabolism, metabolites such as 3-aminoisobutyrate, 3-hydroxyisobutyrate, 2-hydroxyisobutyrate, 3-hydroxyisovalerate, and formate showed no significant associations, as they are primarily associated with amino acid and one-carbon metabolism rather than fiber intake [79,83–86].”
Hepatic Metabolic Profiling of Lifelong Exercise Training Rats
Diamantidou, D., Deda, O., Zervos, I. A., Taitzoglou, I., Gika, H., Theodoridis, G. A., & Michopoulos, F. (2022) · Journal of Proteome Research · doi:10.1021/acs.jproteome.2c00094 · Cited by 5
Katano, S., Yano, T., Kouzu, H., Nagaoka, R., Numazawa, R., Yamano, K., Fujisawa, Y., Ohori, K., Nagano, N., Fujito, T., et al. (2023) · Heart and Vessels · doi:10.1007/s00380-023-02308-y · Cited by 5
“…critical issue, since upregulation of endogenous BAIBA has a therapeutic potential for obesity and its related disorders, such as DM. Plasma BAIBA concentrations have been shown to be increased by acute or chronic exercise in humans, though conflicting data have also been reported [11, 24, 34, 35].”
InfluentialChen, M., Miao, G., Huo, Z., Peng, H. Y., Wen, X., Anton, S. D., Zhang, D., Hu, G., Brock, R., Brantley, P. J., et al. (2024) · Metabolites · doi:10.3390/metabo14020116 · Cited by 4
“It is possible that 3-aminoisobutyric acid may affect glycemic outcomes by increasing fatty acid oxidation and glucose homeostasis through the per-oxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 α )-dependent pathway [43].”
BackgroundLiu, H., Wang, P., Xu, F., Nie, Q., Yan, S., Zhang, Z., Zhang, Y., Jiang, C., Qin, X., & Pang, Y. (2024) · Advanced Science · doi:10.1002/advs.202309525 · Cited by 4
Characteristics of Skeletal Muscle as a Secretory Organ
Aoi, W. (2017) · Springer eBooks · doi:10.1007/978-981-10-3292-9_9 · Cited by 5
Ohnishi, J., Ayuzawa, S., Nakamura, S., Sakamoto, S., Hori, M., Sasaoka, T., Takimoto‐Ohnishi, E., Tanatsugu, M., & Murakami, K. (2017) · Human Genomics · doi:10.1186/s40246-017-0117-3 · Cited by 5
“For example, BAIBA increases the expression of brown-adipocyte-specific genes in white adipocytes and β-oxidation genes in hepatocytes through a peroxisome proliferator-activated receptor alpha (PPARα)-dependent mechanism [42].”
BackgroundAdipose Structure (White, Brown, Beige)
Peirce, V. J., Pellegrinelli, V., & Vidal‐Puig, A. (2016) · Springer eBooks · doi:10.1007/978-3-319-11251-0_23 · Cited by 6
Fukuyama, K., Motomura, E., & Okada, M. (2023) · Nutrients · doi:10.3390/nu15071621 · Cited by 5
“The detailed functions of BAIBA enantiomers had not been clarified for half a century, whereas recently, the function of the BAIBA enantiomer was identified as the protective myokine-like effects that regulate adipose tissue browning, enhanced insulin sensitivity, and suppressed obesity by a high-fat diet [16,17,47].”
BackgroundThe physiological analysis of cross adaptation to regular cold exposure and physical activities
Сонькин, В. Д., Якушкин, А. В., Akimov, E. B., Андреев, Р. С., Каленов, Ю. Н., & Kozlov, A. V. (2014) · Human Physiology · doi:10.1134/s0362119714060103 · Cited by 5
PGC1α and Exercise Adaptations in ZebrafishPreprint
Parisi, A., Blattmann, P., Lizzo, G., Stutz, V., Strohm, L., Richard, J., Civiletto, G., Charpagne, A., Raymond, F., Gobet, C., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/483784 · Cited by 5
“…and metabolomics profiling strategies have been used in mice to identify secreted peptides and metabolites that have systemic effects on energy metabolism (Bostrom et al., 2012; Rao et al., 2014; Roberts et al., 2014), cognitive functions (Wrann et al., 2013), and mood (Agudelo et al., 2014).”
BackgroundÖzöner, M. P., Gür, F. M., Aktaş, İ., Özöner, Ö., & Timurkaan, S. (2026) · Journal of Molecular Histology · doi:10.1007/s10735-026-10719-0 · Cited by 4
“In addition, BAIBA is produced in muscles via peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and passes into adipose tissue, where it increases uncoupling protein 1 (UCP1) expression (Roberts et al. 2014).”
Li, Y., Rao, J., Lai, W., Sun, Y., Lin, H., Zhang, J., Ye, Z., Hu, Z., & Peng, H. (2026) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.70256 · Cited by 4
Exercise-induced myokines in metabolic regulation: mechanisms, mimetics, and translational potential
Aslam, M. A., Lee, J., Bowen, T. S., & Huh, J. Y. (2026) · Archives of Pharmacal Research · doi:10.1007/s12272-026-01624-x · Cited by 7
“…identified as a PGC-1α-associated metabolite released from myocytes that induces thermogenic gene programs in white adipose tissue, stimulates hepatic β-oxidation, improves glucose homeostasis in mice, and is inversely associated with cardiometabolic risk factors in humans (Roberts et al. 2014).”
InfluentialThe Role of Exerkines in Obesity-Induced Disruption of Mitochondrial Homeostasis in Thermogenic Fat
Shao, H., Zhang, H., & Jia, D. (2024) · Metabolites · doi:10.3390/metabo14050287 · Cited by 4
“These hormones include adiponectin, adipsin, fatty acid–binding protein 4 (FABP4), retinol-binding protein 4 (RBP4), chemerin, clusterin, and macrophage migration inhibitory factor [148] (Figure 4)”
BackgroundPanghal, A., & Jena, G. (2024) · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · doi:10.1016/j.mrgentox.2024.503820 · Cited by 4
Liu, R., Xi, Y., Duan, X., Zhao, Y., & Tian, Z. (2025) · Life Sciences · doi:10.1016/j.lfs.2025.123628 · Cited by 4
A comprehensive model for the converging biologies that underpin the homeostatic sleep signal
Fernandez, F., & Grandner, M. A. (2025) · Sleep Medicine · doi:10.1016/j.sleep.2025.106723 · Cited by 4
Bonewald, L. F. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-813073-5.00007-1 · Cited by 8
Circulating dimethylguanidino valeric acid, dietary factors, and risk of coronary heart disease
Heianza, Y., Wang, X., Kou, M., Tiwari, S., Watrous, J. D., Rexrode, K. M., Alotaibi, M., Jain, M., Sun, Q., Manson, J. E., et al. (2024) · Cardiovascular Research · doi:10.1093/cvr/cvae199 · Cited by 4
Muscle PGC‐1α Overexpression Drives Metabolite Secretion Boosting Subcutaneous Adipocyte Browning
Miro, C., Menale, C., Acampora, L., Nappi, A., Sagliocchi, S., Restolfer, F., Torabinejad, S., Stornaiuolo, M., Dentice, M., & Cicatiello, A. G. (2024) · Journal of Cellular Physiology · doi:10.1002/jcp.31480 · Cited by 4
Can Exercise-Mediated Adipose Browning Provide an Alternative Explanation for the Obesity Paradox?
Zhao, J., Li, X., Liang, C., & Yan, Y. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26051790 · Cited by 5
In-Vivo Degradation of DNA-Based Therapeutic BC 007 in Humans
Davideit, H., Becker, S., Müller, J., Becker, N., Göttel, P., Abay, A., Sinn, A., Grossmann, M., Mallek, M., Haberland, A., et al. (2019) · European Journal of Drug Metabolism and Pharmacokinetics · doi:10.1007/s13318-019-00541-3 · Cited by 4
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Myokines: A potential key factor in development, treatment, and biomarker of sarcopenia
Aoi, W. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-822146-4.00006-5 · Cited by 4
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ERRα Attenuates Vascular Inflammation via Enhanced NFκB Degradation Pathway
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Leucine Supplementation Ameliorates Early-Life Programming of Obesity in Rats
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Factors Regulating Uncoupling Protein-3 (UCP-3) Expression in Skeletal Muscle
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Skeletal Muscle Metabolomics for Metabolic Phenotyping and Biomarker Discovery
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Current Progress in Adipose Tissue Biology: Implications in Obesity and Its Comorbidities
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Metadata
- Authors
- Roberts, L. D., Boström, P., O’Sullivan, J. F., Schinzel, R. T., Lewis, G. D., Dejam, A., Lee, Y.-K., Palma, M. J., Calhoun, S., Georgiadi, A., Chen, M.-H., Ramachandran, V. S., Larson, M. G., Bouchard, C., Rankinen, T., Souza, A. L., Clish, C. B., Wang, T. J., Estall, J. L., Soukas, A. A., Cowan, C. A., Spiegelman, B. M., & Gerszten, R. E.
- Affiliations
- Harvard University (US)
- Broad Institute (US)
- Karolinska Institutet (SE)
- Boston University (US)
- Pennington Biomedical Research Center (US)
- Montreal Clinical Research Institute (CA)
- Corresponding author
- Gerszten, Robert E.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2014-01
- Volume
- 19
- Issue
- 1
- Pages
- 96-108
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4017355
- OpenAlex
- W1974559463
- Cited by
- 643
- References
- 62
- Citations by year
- 2026: 49 · 2025: 46 · 2024: 57 · 2023: 62 · 2022: 65 · 2021: 51 · 2020: 55 · 2019: 59 · 2018: 50 · 2017: 34 · 2016: 51 · 2015: 42 · 2014: 21
- FWCI
- 32.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (n01hc25195-41-0-1)
- National Heart, Lung, and Blood Institute (N01‐HC25195, R01HL098280, N01-HC-025195, R01HL045670)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK095384, R01DK031405, DK-31405, R37DK031405, R01DK081572)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- beta-aminoisobutyric acid, myokines, PGC-1α, brown adipose tissue browning, white adipose tissue, hepatic beta-oxidation, PPARα, physical activity, glucose homeostasis, cardiometabolic risk factors
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Aminoisobutyric Acids, Animals, Adipose Tissue, Brown, Cardiovascular Diseases, Cell Differentiation, Gene Expression Regulation, Glucose Tolerance Test, Humans, Liver, Metabolic Diseases, Organ Specificity, Oxidation-Reduction, Phenotype, Physical Conditioning, Animal, Risk Factors, Transcription Factors, Transcription, Genetic, Weight Gain, Exercise, PPAR alpha, Mice, Adipose Tissue, White, Adipocytes, Brown, Adipocytes, White, Induced Pluripotent Stem Cells
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