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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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In the citing paper
“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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“Finally, the authors suggesting that BAIBA is a myokine found that, in humans, BAIBA levels were inversely correlated to cardiometabolic risk factors (Roberts et al., 2014).”
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“These include for instance metorin-like 1 [112], myostatin [113], and β-aminoisobutyric acid [114].”
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Brown and Beige Adipose Tissue
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“These “exerkines,” briefly described above, include small molecule metabolites and proteins secreted from skeletal muscle (myokines), adipose tissue, liver, and even bone, and work in a autocrine, paracrine, and endocrine fashion.(88,91,173,174) The realization of multilevel, scalable molecular profiling techniques co…”
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“Cold exposure [16,17,37,38,65,75,76] Methionine restriction [193,195,196] 3-AR agonists [16,38,67–69,71,77,78] Leucine restriction [199,200] Adenosine receptor agonists [81] In utero dietary restriction [204] BAIBA [125,130] Lactate [137] BMP [141,142] Ketone bodies [137,221] Cannabinoid receptor inverse agonist [89,9…”
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Prdm4 induction by the small molecule butein promotes white adipose tissue browning
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Browning of Adipocytes: A Potential Therapeutic Approach to Obesity
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“These myokines, identified in early 2014, are as follows: irisin, β-aminoisobutyric acid (BAIBA) and FGF21; these would appear to govern white adipocyte browning, independent of sympathetic nervous system stimulation [39,40].”
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“Moreover, PGC-1α binds PPARγ and stimulates the browning of white adipose tissue, mitochondrial biogenesis and respiratory functions that facilitate energy expenditure (Roberts et al., 2014; Wenz et al., 2016).”
BackgroundAn overview of energy and metabolic regulation
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The role of brown and beige adipose tissue in glycaemic control
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“…other factors that promote browning are also altered during or following exercise, such as interleukin-6 (Ma et al., 2015), B-aminoisobutyric acid (Roberts et al., 2014), meteorin-like (Rao et al., 2014), FGF21 (Giralt et al., 2015), natriuretic peptides (NP's) (Bordbar et al., 2012; Follenius…”
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“In the muscle, the predicted production of 3-amino-isobutyrate (BAIBA, 3aib) is consistent with this molecule being secreted to blood during exercise in humans (Roberts et al , 2014).”
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Circadian Regulation of Metabolism: Commitment to Health and Diseases
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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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