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A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis
Open accessAbstract
Exercise benefits a variety of organ systems in mammals, and some of the best-recognized effects of exercise on muscle are mediated by the transcriptional co-activator PPAR-γ co-activator-1 α (PGC1-α). Here we show in mouse that PGC1-α expression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown-fat-like development. Irisin is induced with exercise in mice and humans, and mildly increased irisin levels in the blood cause an increase in energy expenditure in mice with no changes in movement or food intake. This results in improvements in obesity and glucose homeostasis. Irisin could be therapeutic for human metabolic disease and other disorders that are improved with exercise.
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“When originally described, it was found to exert browning of WAT, increase energy expenditure, improve insulin sensitivity, and induce weight loss, through upregulation of UCP1 in exercised mice overexpressing PGC-1α [57].”
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 [57]
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 [57]
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
“FNDC-5 is known to drive development of brown-fat-like cells in WAT, which enhances lipid metabolism/oxidation via mitochondrial uncoupling protein 1 (UCP-1) activity [12].”
From β-hydroxy-β -methylbutyrate supplementation benefits the effects of resistance training on body fat reduction via increased irisin expression in white adipose tissue (2021) · cites this paper as [12]
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
“However, only the irisin precursor FNDC5 was able to promote the differentiation of stromal vascular cells isolated from WAT from beige mice (browning phenomenon; Bostrom et al., 2012).”
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 Bostrom et al., 2012
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Irisin is a myokine that promotes white adipose tissue browning, originally identified through animal studies [38] and subsequently confirmed in humans [39].”
From Exercise-Induced Myokines in Obesity-Related Metabolic Disorders and Cardiovascular Protection: A Narrative Review (2026) · cites this paper as [38]
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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
“Irisin is stimulated by ‘Peroxisome proliferator-activated receptor-Gamma Coactivator 1α’ (PGC1α), and mediates beneficial metabolic effects through the beiging of white AT [17,49], thereby activating UCP1 and inducing enhanced thermogenesis within the white AT.”
From Optimised Skeletal Muscle Mass as a Key Strategy for Obesity Management (2025) · cites this paper as [49]
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In the citing paper
“Thus, following the characterization of irisin as a myokine capable of activating adipose tissue browning in rodents in response to exercise (Bostrom et al., 2012) the concept that factors secreted by SkM could signal to other organs has grown and developed.”
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 Bostrom et al., 2012
The cited source says what the claim attributes to it.
In the citing paper
“Irisin, formerly called Iris, is a recently identified myokine, released into the circulation by SkM in an exercise-dependent manner.”
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 Bostrom et al., 2012
The cited source says what the claim attributes to it.
In the citing paper
“It is reported to have the ability to convert WAT to BAT, a phenomenon known as browning; a phenotype set of adaptations that results in increasing total energy expenditure (Bostrom et al., 2012).”
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 Bostrom et al., 2012
The cited source says what the claim attributes to it.
In the citing paper
“Five candidate proteins were found to be mediated by PGC-1α in the muscle: IL-15, Fndc5, VEGFβ, Lrg1, and TIMP4.”
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 Bostrom et al., 2012
The cited source says what the claim attributes to it.
In the citing paper
“Other papers have demonstrated that exercise induces upregulation in skeletal muscle of PGC1α, a transcriptional co-activator of mitochondrial biogenesis and oxidative metabolism in brown adipose tissue and muscle. In muscle, the increase of PGC1α expression stimulates an upregulation of FNDC5, a membrane protein that is cleaved and secreted into the circulation as the myokine irisin [237].”
From Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer (2020) · cites this paper as [237]
In the citing paper
“Irisin is a PPARγ-coactivator-1α (PGCα)-dependent myokine that stimulates browning in subcutaneous adipose tissues and induces increased energy expenditure, which improves obesity and IR through the MAPK and ERK pathways [92,93].”
From Sarcopenic obesity, insulin resistance, and their implications in cardiovascular and metabolic consequences (2020) · cites this paper as [92]
In the citing paper
“Irisin is released by skeletal muscles and has been shown to increase thermogenesis and energy expenditure by promoting the browning of subcutaneous adipocytes.”
From Diet and physical exercise as key players to tackle MASLD through improvement of insulin resistance and metabolic flexibility (2024) · cites this paper as [88]
In the citing paper
“Moreover, resistance exercise may improve MASLD through muscle-liver crosstalk mediated by a myokine called irisin (88, 89).”
From Diet and physical exercise as key players to tackle MASLD through improvement of insulin resistance and metabolic flexibility (2024) · cites this paper as [88]
In the citing paper
“It also exhibits regulatory effects on lipid metabolism in hepatocytes (88).”
From Diet and physical exercise as key players to tackle MASLD through improvement of insulin resistance and metabolic flexibility (2024) · cites this paper as [88]
In the citing paper
“The main and well-described function of irisin is to induce WAT browning and thus UCP-1-dependent mitochondrial uncoupling [206].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [206]
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 [84]
In the citing paper
“Transgenic mice that overexpress muscle peroxisome proliferator-activated receptor-γ coactivator 1-α (PGClα) have higher circulating levels of irisin and increased WAT browning than control mice84.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [84]
In the citing paper
“In a mouse model, fibronectin type III domain containing 5 is cleaved in the muscle cell and secreted as irisin, which induces WAT browning to increase energy expenditure and consequently reduce obesity84.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [84]
In the citing paper
“The first paper to describe irisin, a PGC1α-dependent myokine, that drives ‘browning’ of WAT in an animal model”
From Exerkines in health, resilience and disease (2022) · cites this paper as [84]
In the citing paper
“FNDC5 induces thermogenesis and elevates mitochondrial gene expression [131], and resilient mice have increased NAc metabolism [132].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [131]
In the citing paper
“recent studies have identified secreted proteins that stimulate brown adipocyte thermogenesis and recruit brown (or beige) adipocytes to white adipose tissue [60] [61].”
From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [61]
In the citing paper
“Interestingly, a moderate increase (threefold) in irisin blood levels in mice enhanced energy expenditure and improved obesity and glucose homeostasis ([12](#B12)).”
From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [12]
In the citing paper
“Recent landmark studies have identified novel secreted proteins, such as liver FGF21 ([72](#B72)), cardiac natriuretic peptides ([11](#B11)), and irisin ([12](#B12)), that stimulate brown adipocyte thermogenesis.”
From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [12]
In the citing paper
“Irisin was shown to trigger WAT remodeling by increasing p38 signaling, UCP1 expression, and therefore browning 115, 116.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [115]
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“Irisin Ob: ↑ [39]+; T2DM: ↓ [39]+ AE: ↑ (aerobic or resistance) [40]+ CE: ↓? (aerobic or resistance) [41]+ ↑ (via PGC-1α): cold-induced shivering [42], ↑AMP:ATP ratio (via AMPK-PGC-1α pathway), FGF21* [43], and METRNL (via ↑PGC-1α4)* [44] ↓: proinflammatory cytokines [45] (possibly via NF-kB-mediated inhibition of PGC…”
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Self-citation
Metadata
- Authors
- Boström, P., Wu, J., Jedrychowski, M. P., Korde, A., Ye, L., Lo, J. C., Rasbach, K. A., Boström, E. A., Choi, J. H., Long, J. Z., Kajimura, S., Zingaretti, M. C., Vind, B. F., Tu, H., Cinti, S., Højlund, K., Gygi, S. P., & Spiegelman, B. M.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- University of California, San Francisco (US)
- Marche Polytechnic University (IT)
- Odense University Hospital (DK)
- LakePharma (United States) (US)
- Corresponding author
- Spiegelman, Bruce M.
- ORCID
- Venue
- Nature
- Published
- 2012-01
- Volume
- 481
- Issue
- 7382
- Pages
- 463-468
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3522098
- OpenAlex
- W2085397620
- Cited by
- 4,810
- References
- 26
- Citations by year
- 2026: 309 · 2025: 347 · 2024: 361 · 2023: 392 · 2022: 453 · 2021: 408 · 2020: 393 · 2019: 331 · 2018: 318 · 2017: 294 · 2016: 275 · 2015: 292 · 2014: 283 · 2013: 229 · 2012: 120
- FWCI
- 198.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion)
- Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (K99DK087853, DK54477, R56DK054477, R01DK031405, DK-31405, R01DK061562, R01DK054477, R37DK031405)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- irisin, FNDC5, PGC-1α, myokines, brown adipose tissue browning, white adipose tissue, thermogenesis, UCP1, physical activity, energy expenditure, obesity, glucose homeostasis, type 2 diabetes, metabolic disease treatment
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Uncoupling Protein 1, Animals, Adipose Tissue, Brown, Cells, Cultured, Energy Metabolism, Gene Expression Regulation, Hormones, Humans, Insulin Resistance, Ion Channels, Mice, Inbred BALB C, Mice, Transgenic, Obesity, Physical Conditioning, Animal, Plasma, Transcription Factors, Exercise, Trans-Activators, Culture Media, Conditioned, Adipocytes, Cell Respiration, Thermogenesis, Models, Animal, Mitochondrial Proteins, Muscle Cells, Intracellular Signaling Peptides and Proteins, Subcutaneous Fat, Mice, Adipose Tissue, White
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