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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.
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“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.
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“which is known to upregulate the WAT browning myokines FNDC5-irisin [57], METRNL [274], and BAIBA [104].”
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“For instance, BAIBA [104] and FGF21 [160] have been shown to increase hepatic β-oxidation (6)”
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“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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Advances in the research on myokine-driven regulation of bone metabolism
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“ROS are critical for the maintenance of mitochondrial function [34].”
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“Indeed, an emerging theme in homeostatic feedback is the recognition of metabolites as signaling effectors between tissues as means of physiologic integration within the body [see (Blad et al , 2012; Liu et al , 2013; Roberts et al , 2014) for examples].”
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“PGC-1α can increase the β-oxidation of hepatocytes through Pparα [58].”
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“Muscle cells and BAT come from the same source, and exercise can actively promote the expression of myogenic cytokines Irisin [36] and β-amino-isobutyric acid (BAIBA) [37], and the activation of BAT can also be realized through Irisin and Sirt1 signalling pathways.”
BackgroundExercise‐Induced cytokines, diet, and inflammation and their role in adipose tissue metabolism
Al‐Ibraheem, A. M. T., Hameed, A. A. Z., Marsool, M. D. M., Jain, H., Prajjwal, P., Khazmi, I., Nazzal, R., Al-Najati, H. M. H., Al‐Zuhairi, B. H. Y. K., Razzaq, M., et al. (2024) · Health Science Reports · doi:10.1002/hsr2.70034 · Cited by 33
“43 BAIBA is associated with higher plasma leptin levels and fatty acid oxidation in mice.”
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Does inorganic nitrate say NO to obesity by browning white adipose tissue?
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Garnham, J. O., Roberts, L. D., Caspi, T., Al‐Owais, M. M., Bullock, M., Swoboda, P., Koshy, A. O., Gierula, J., Paton, M. F., Cubbon, R. M., et al. (2019) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12488 · Cited by 28
Molecular Signature of Multisystem Cardiometabolic Stress and Its Association With Prognosis
Murthy, V. L., Yu, B., Wang, W., Zhang, X., Alkis, T., Pico, A. R., Yeri, A., Bhupathiraju, S. N., Bressler, J., Ballantyne, C. M., et al. (2020) · JAMA Cardiology · doi:10.1001/jamacardio.2020.2686 · Cited by 27
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“ALK7 = activin receptor‐like kinase 7; HSL = hormone‐sensitive lipase; ATGL = adipose triglyceride lipase; UCP1 = uncoupling protein 1; PRDM16 = PRD1‐BF1‐RIZ1 homologous domain containing 16; PPARα = peroxisome proliferator‐activated receptor‐α; CPT‐1α = carnitine palmitoyltransferase 1α; TNF‐α = tumor necrosis factor…”
BackgroundInfluentialExercise-induced crosstalk between immune cells and adipocytes in humans: Role of oncostatin-M
Dollet, L., Lundell, L. S., Chibalin, A., Pendergrast, L. A., Pillon, N. J., Lansbury, E., Elmastas, M., Frendo‐Cumbo, S., Jalkanen, J., Barbosa, T. D. C., et al. (2023) · Cell Reports Medicine · doi:10.1016/j.xcrm.2023.101348 · Cited by 28
Sarcopenic obesity and osteoporosis: Research progress and hot spots
Fan, S., Cai, Y., Wei, Y., Yang, J., Gao, J., & Yang, Y. (2024) · Experimental Gerontology · doi:10.1016/j.exger.2024.112544 · Cited by 29
Exercise, Neuroprotective Exerkines, and Parkinson’s Disease: A Narrative Review
Mitchell, A. K., Bliss, R. R., & Church, F. (2024) · Biomolecules · doi:10.3390/biom14101241 · Cited by 33
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Hahn, A. K., Batushansky, A., Rawle, R. A., Lopes, E. B. P., June, R. K., & Griffin, T. M. (2021) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2021.08.008 · Cited by 26
Probing metabolic memory in the hepatic response to fasting
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Yu, Y., Chen, W., Yu, M., Liu, J., Sun, H., & Yang, P. C. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.803510 · Cited by 25
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Rodgers, M., Migdal, A. L., Rodríguez, T. G., Chen, Z.-Z., Nath, A. K., Gerszten, R. E., Kasid, N., Toschi, E., Tripaldi, J., Heineman, B., et al. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.742873 · Cited by 24
“Notably, aminoisobutryric acid increases following exercise and induces browning of white fat (32).”
BackgroundInter-organ metabolic interaction networks in non-alcoholic fatty liver disease
Fan, Y., Zhang, S., Wang, Y., Wang, H., Li, H., & Bai, L. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1494560 · Cited by 25
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“Another valine metabolite, β-aminoisobutyric acid, improved glucose homeostasis in mice (57).”
BackgroundMetabolic factors in the regulation of hypothalamic innate immune responses in obesity
Folick, A., Cheang, R. T., Valdearcos, M., & Koliwad, S. K. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00666-z · Cited by 26
Effects of Muscles on Bone Metabolism—with a Focus on Myokines
Kim, B. (2022) · Annals of Geriatric Medicine and Research · doi:10.4235/agmr.22.0054 · Cited by 26
Exercise-Induced Adipose Tissue Thermogenesis and Browning: How to Explain the Conflicting Findings?
Zhu, Y., Qi, Z., & Ding, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113142 · Cited by 27
“BAIBA supplementation increased UCP1 and Cidea expression via the PPARα pathway, and accelerated fatty acid oxidation in the liver and thus reduced body fat [65].”
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“adaptations in multiple tissues, impacting whole-body physiology through the secretion of diverse molecules, such as growth factors 13–15 , cytokines 13 , microRNAs 16,17 , and metabolites 18,19 .”
BackgroundImportance of adipocyte browning in the evolution of endothermy
Jastroch, M., & Seebacher, F. (2020) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2019.0134 · Cited by 23
“Additionally, small metabolites such as lactate and β-aminoisobutyric acid can act as browning agents [84,85].”
BackgroundBAIBA does not regulate UCP-3 expression in human skeletal muscle as a response to aerobic exercise
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Dietary Components, Microbial Metabolites and Human Health: Reading between the Lines
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Metabokines in the regulation of systemic energy metabolism
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Skeletal muscle-secreted DLPC orchestrates systemic energy homeostasis by enhancing adipose browning
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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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