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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]
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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].”
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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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“BAIBA induces an increase in thermogenic gene ex- pression in WAT through a specific PPARα‐dependent mechanism (Roberts et al., 2014).”
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Whitehead, A., Krause, F. N., Moran, A., MacCannell, A. D. V., Scragg, J. L., McNally, B. D., Boateng, E. A., Murfitt, S. A., Virtue, S., Wright, J., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22272-3 · Cited by 166
Metabolic communication during exercise
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Postmenopausal osteoporosis coexisting with sarcopenia: the role and mechanisms of estrogen
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The circulating metabolome of human starvation
Steinhauser, M. L., Olenchock, B. A., O’Keefe, J., Lun, M., Pierce, K. A., Lee, H., Pantano, L., Klibanski, A., Shulman, G. I., Clish, C. B., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.121434 · Cited by 157
“BAIBA has also been shown in other contexts to augment fatty acid oxidation and ketogenesis (20, 21).”
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Renal metabolism and hypertension
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Barquissau, V., Beuzelin, D., Pisani, D. F., Béranger, G. E., Mairal, A., Montagner, A., Roussel, B., Tavernier, G., Marques, M.-A., Moro, C., et al. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2016.03.002 · Cited by 154
Sarcopenia and Cognitive Function: Role of Myokines in Muscle Brain Cross-Talk
Scisciola, L., Fontanella, R. A., Surina, S., Cataldo, V., Paolisso, G., & Barbieri, M. (2021) · Life · doi:10.3390/life11020173 · Cited by 153
Dimethylguanidino valeric acid is a marker of liver fat and predicts diabetes
O’Sullivan, J., Morningstar, J. E., Yang, Q., Zheng, B., Gao, Y. L., Jeanfavre, S., Scott, J. M., Fernandez, C., Zheng, H., O’Connor, S., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci95995 · Cited by 136
“org Volume 127 Number 12 December 2017 opment, decreased DDAH1 enzymatic activity (34–36) and decreased BAIBA levels in cardiometabolic disease (32) lead to an increased concentration of ADMA that binds AGXT2 more freely (due to decreased levels of BAIBA, the major substrate of AGXT2) and thereby leads to increased co…”
BackgroundA muscle-liver-fat signalling axis is essential for central control of adaptive adipose remodelling
Shimizu, N., Maruyama, T., Yoshikawa, N., Matsumiya, R., Ma, Y., Ito, N., Tasaka, Y., Souta-Kuribara, A., Miyata, K., Oike, Y., et al. (2015) · Nature Communications · doi:10.1038/ncomms7693 · Cited by 138
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“This metabolite also induces BAT-like phenotype in human pluripotent stem cells [309] Retinoic acid stimulates WAT browning by increasing vascular endothelial growth factor signaling and promoting beige adipogenesis of PDGFRα + adipose progenitors [310] Other factors: Gut microbiota Gut microbiota…”
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The search for exercise factors in humans
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Impaired proteostasis during skeletal muscle aging
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Exercise regulation of adipose tissue
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Myokines in skeletal muscle physiology and metabolism: Recent advances and future perspectives
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Sánchez‐Delgado, G., Martínez‐Téllez, B., Olza, J., Aguilera, C. M., Labayen, I., Ortega, F. B., Chillón, P., Fernandez-Reguera, C., Alcántara, J. M. A., Martinez-Avila, W. D., et al. (2015) · Contemporary Clinical Trials · doi:10.1016/j.cct.2015.11.004 · Cited by 135
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Mechanisms by Which Skeletal Muscle Myokines Ameliorate Insulin Resistance
Balakrishnan, R., & Thurmond, D. C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094636 · Cited by 143
Systemic Nutrient and Stress Signaling via Myokines and Myometabolites
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Bone and Muscle Crosstalk in Aging
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“Reports have shown that BAIBA improves metabolism dependent on PPAR and leptin (Kammoun and Febbraio, 2014; Roberts et al., 2014).”
BackgroundBeta-Aminoisobutyric Acid as a Novel Regulator of Carbohydrate and Lipid Metabolism
Tanianskii, D. A., Jarzebska, N., Birkenfeld, A. L., O’Sullivan, J. F., & Rodionov, R. N. (2019) · Nutrients · doi:10.3390/nu11030524 · Cited by 121
“Roberts et al., 2014 revealed that the transcriptional coactivator PGC-1α, which is induced in muscles by physical exercise, stimulates BAIBA production, possibly through expression of enzymes responsible for valine catabolism [22].”
BackgroundExercise-induced adaptations to white and brown adipose tissue
Lehnig, A. C., & Stanford, K. I. (2018) · Journal of Experimental Biology · doi:10.1242/jeb.161570 · Cited by 127
“…(Boström et al., 2012), myostatin (Feldman et al., 2006), meteorin-like 1 (Metrnl) (Rao et al., 2014), lactate (Carriere et al., 2014) and βaminoisobutyric acid (BAIBA) (Roberts et al., 2014), as well as other secreted factors, including brain-derived neurotrophic factor (BDNF) (Cao et al., 2011).”
BackgroundEngineered skeletal muscles for disease modeling and drug discovery
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Role of Exercise in the Activation of Brown Adipose Tissue
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Muscle-Adipose Tissue Cross TalkPreprint
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“The role of Metrnl in exercise-induced beiging in human scWAT requires future investigation. b-Aminoisobutyric Acid BAIBA (Roberts et al. 2014) is another myokine that has been recently identified to have a role in the beiging of scWAT after exercise.”
InfluentialGinsenoside Rb1 promotes browning through regulation of PPARγ in 3T3-L1 adipocytes
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Myokines in metabolic homeostasis and diabetes
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“For example, molecules released from skeletal muscle, such as β-aminoisobutyric acid [9] and lactate [10], were shown to convey signalling to the liver, adipose tissue and the brain [11].”
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HDAC11 suppresses the thermogenic program of adipose tissue via BRD2
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Beiging of white adipose tissue as a therapeutic strategy for weight loss in humans
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Human Brown Adipose Tissue and Metabolic Health: Potential for Therapeutic Avenues
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The Beige Adipocyte as a Therapy for Metabolic Diseases
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New therapeutic approaches for the treatment of obesity
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Can exercise affect the course of inflammatory bowel disease? Experimental and clinical evidence
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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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