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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Irisin was originally found to exert browning of white adipose tissue, increase energy expenditure, improve insulin sensitivity, and induce weight loss through upregulation of UCP1 in exercised mice overexpressing PGC-1α.
“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]
The section “Irisin reduces diet-induced obesity and insulin resistance in vivo” reports increased UCP1 expression and oxygen consumption, improved glucose tolerance, reduced fasting insulin, and slight weight loss in high-fat-fed mice given Fndc5-expressing adenovirus (page unavailable). The cited paper also links irisin to exercise and muscle PGC1α, but it does not report that this full set of outcomes was observed in exercised mice overexpressing PGC1α. (LLM, conf=0.89)
Experimental — accuracy not yet measuredThe myokines irisin and BAIBA directly induce WAT browning both in vitro and in vivo by upregulating genes involved in mitochondrial biogenesis, FAO, oxidative phosphorylation, and thermogenesis.
“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]
The Abstract and the section on cultured white adipose cells report that irisin/Fndc5 induces browning in vitro and in vivo, with increased UCP1 and mitochondrial gene expression. The cultured-cell section also reports increased mitochondrial density and a thermogenic gene program, but the passages do not establish upregulation of fatty-acid-oxidation genes. This citation is attached to irisin; BAIBA has a separate citation and is not assessed here. (LLM, conf=0.84)
Experimental — accuracy not yet measuredFNDC-5 drives development of brown-fat-like cells in white adipose tissue, which enhances lipid metabolism/oxidation via mitochondrial uncoupling protein 1 activity.
“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]
The section on cultured white adipose cells reports that Fndc5 induces a brown-fat-like phenotype, increases UCP1 expression, and raises largely uncoupled oxygen consumption. The in-vivo section also reports browning of subcutaneous white fat. Neither passage establishes increased lipid oxidation specifically through UCP1 activity; the paper measures UCP1 expression and respiration, not that causal link. (LLM, conf=0.85)
Experimental — accuracy not yet measuredOnly the irisin precursor FNDC5 was able to promote differentiation of stromal vascular cells isolated from white adipose tissue from beige mice (browning).
“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
The Results section, “Fndc5 robustly induces a brown fat gene program in cultured white adipose cells” (page not available), reports that Fndc5 induced browning markers during differentiation of primary white-fat cells. But “only” is too strong: the same section reports a smaller effect from BMP-7. The Methods section, “Primary cell cultures and recombinant protein treatments” (page not available), identifies the stromal-vascular cells as coming from inguinal fat of BALB/C mice, not mice described as beige. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIrisin promotes white adipose tissue browning, originally identified through animal studies and subsequently confirmed in humans.
“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]
PGC-1α upregulates the WAT browning myokines FNDC5-irisin, METRNL, and BAIBA.
“which is known to upregulate the WAT browning myokines FNDC5-irisin [57], METRNL [274], and BAIBA [104].”
Irisin is stimulated by PGC1α, and mediates beneficial metabolic effects through the beiging of white AT, thereby activating UCP1 and inducing enhanced thermogenesis within the white AT.
“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]
Following the characterization of irisin as a myokine capable of activating adipose tissue browning in rodents in response to exercise, the concept that factors secreted by skeletal muscle could signal to other organs has grown and developed.
“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
Irisin is released into the circulation by skeletal muscle in an exercise-dependent manner.
“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
Irisin has the ability to convert white adipose tissue to brown adipose tissue (browning), a phenotype that results in increasing total energy expenditure.
“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
In a study seeking to elucidate the relevance of PGC-1α in control of obesity, an algorithm predicted five candidate proteins produced by skeletal muscle that may mediate browning in adipose tissue: IL-15, Fndc5, VEGFβ, Lrg1, and TIMP4.
“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
Exercise induces upregulation in skeletal muscle of PGC1α, which stimulates upregulation of FNDC5, cleaved and secreted into the circulation as the myokine irisin.
“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]
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.
“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]
Irisin is released by skeletal muscles and increases thermogenesis and energy expenditure by promoting browning of subcutaneous adipocytes.
“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]
Resistance exercise may improve MASLD through muscle-liver crosstalk mediated by irisin.
“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]
Irisin exhibits regulatory effects on lipid metabolism in hepatocytes.
“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]
The main and well-described function of irisin is to induce WAT browning and thus UCP-1-dependent mitochondrial uncoupling.
“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]
Whether exercise can brown WAT in humans, especially through an irisin-mediated pathway, remains controversial.
“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]
Transgenic mice overexpressing muscle PGC1α have higher circulating irisin and increased WAT browning than controls.
“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 a mouse model, irisin is cleaved from fibronectin type III domain containing 5 in muscle and secreted, inducing WAT browning to increase energy expenditure and reduce obesity.
“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]
Irisin is a PGC1α-dependent myokine that drives browning of white adipose tissue in an animal model.
“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]
FNDC5 induces thermogenesis and elevates mitochondrial gene expression.
“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]
Secreted proteins stimulate brown adipocyte thermogenesis and recruit brown or beige adipocytes to white adipose tissue.
“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]
A moderate increase (threefold) in irisin blood levels in mice enhanced energy expenditure and improved obesity and glucose homeostasis.
“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]
Recent landmark studies have identified novel secreted proteins, such as liver FGF21, cardiac natriuretic peptides, and irisin, that stimulate brown adipocyte thermogenesis.
“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]
Irisin triggers WAT remodeling by increasing p38 signaling, UCP1 expression, and therefore browning.
“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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- 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 › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › 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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