Progress and Challenges in the Biology of FNDC5 and Irisin
Open accessAbstract
In 2002, a transmembrane protein-now known as FNDC5-was discovered and shown to be expressed in skeletal muscle, heart, and brain. It was virtually ignored for 10 years, until a study in 2012 proposed that, in response to exercise, the ectodomain of skeletal muscle FNDC5 was cleaved, traveled to white adipose tissue, and induced browning. The wasted energy of this browning raised the possibility that this myokine, named irisin, might mediate some beneficial effects of exercise. Since then, more than 1000 papers have been published exploring the roles of irisin. A major interest has been on adipose tissue and metabolism, following up the major proposal from 2012. Many studies correlating plasma irisin levels with physiological conditions have been questioned for using flawed assays for irisin concentration. However, experiments altering irisin levels by injecting recombinant irisin or by gene knockout are more promising. Recent discoveries have suggested potential roles of irisin in bone remodeling and in the brain, with effects potentially related to Alzheimer's disease. We discuss some discrepancies between research groups and the mechanisms that are yet to be determined. Some important questions raised in the initial discovery of irisin, such as the role of the mutant start codon of human FNDC5 and the mechanism of ectodomain cleavage, remain to be answered. Apart from these specific questions, a promising new tool has been developed-mice with a global or tissue-specific knockout of FNDC5. In this review, we critically examine the current knowledge and delineate potential solutions to resolve existing ambiguities.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Irisin 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 [39]
The citation is attached to the claim that irisin-induced browning was subsequently confirmed in humans. The paper’s “Irisin, Exercise, and Browning of WAT” section says browning was induced in mice but “was not shown in humans so far”; it also says there is very little evidence that exercise-induced WAT browning extends to humans. (LLM, conf=0.94)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredIn animal models and human cell studies, irisin acts on white adipose tissue to induce browning, increasing expression of thermogenic proteins such as UCP1 and thereby promoting energy expenditure.
“In animal models and human cell studies, irisin has been shown to act on white adipose tissue to induce “browning”—increasing expression of thermogenic proteins such as UCP1—thereby promoting energy expenditure [39].”
From Exercise-Induced Myokines in Obesity-Related Metabolic Disorders and Cardiovascular Protection: A Narrative Review (2026) · cites this paper as [39]
The ‘Irisin, Exercise, and Browning of WAT’ section (page unavailable) reports that FNDC5 manipulation induces UCP1 expression and browning in mice, and explains that UCP1 can dissipate energy as heat. But the review does not establish the claimed browning in human cell studies; its Figure 3 caption says it had not been shown in humans, and ‘Unsolved Issues’ says human intervention studies found no irisin-related increase in energy expenditure. The sentence presents those effects more conclusively than the source does. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIrisin synthesis is directly coupled to exercise via PGC1α upregulation during muscle contraction, which enhances FNDC5 expression followed by proteolytic cleavage and release of irisin into circulation.
“Its synthesis is directly coupled to exercise via PGC1α upregulation during muscle contraction, which enhances FNDC5 expression followed by proteolytic cleavage and release of irisin into circulation [39].”
From Exercise-Induced Myokines in Obesity-Related Metabolic Disorders and Cardiovascular Protection: A Narrative Review (2026) · cites this paper as [39]
The 'Irisin, Exercise, and Browning of WAT' section (page not provided) says exercise increases muscle PGC-1α and describes increased FNDC5 and cleavage as a proposed pathway. It says exercise-induced FNDC5 increases are established in mice but not humans, while the cleavage mechanism and irisin response to exercise remain uncertain. The claim presents the entire pathway as established and directly coupled to exercise. (LLM, conf=0.90)
Experimental — accuracy not yet measuredMechanical load promotes protein synthesis via the mTORC1 pathway and upregulates PGC-1α-dependent irisin secretion.
“Concurrently, mechanical load promotes protein synthesis via the mTORC1 pathway and upregulates PGC-1α-dependent irisin secretion [39].”
From Exercise-Induced Myokines in Obesity-Related Metabolic Disorders and Cardiovascular Protection: A Narrative Review (2026) · cites this paper as [39]
The “Irisin, Exercise, and Browning of WAT” section (page unavailable) says exercise-induced PGC-1α was proposed to increase FNDC5 and its cleavage to irisin. It also says the irisin response to exercise remains controversial. The cited paper does not establish that mechanical load increases irisin secretion or support the claimed mTORC1-mediated protein synthesis. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 162 · Cited by 247
Research works printed but not linked: 2
- [110]Pang M, Yang J, Rao J, et al. Time-Dependent Changes in Increased Levels of Plasma Irisin and Muscle PGC-1α and FNDC5 after Exercise in Mice. Tohoku J Exp Med. 2018; 244(2): 93- 103. 29415899
- [115]Zhang Y, Li R, Meng Y, et al. Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling. Diabetes. 2014; 63(2): 514- 525. 24150604 PMC13117908
- Authors
- Maak, S., Norheim, F., Drevon, C. A., & Erickson, H. P.
- Affiliations
- Research Institute for Farm Animal Biology (FBN) (DE)
- University of Oslo (NO)
- Duke University (US)
- Corresponding author
- Maak, Steffen
- Venue
- Endocrine Reviews
- Publisher
- The Endocrine Society
- Published
- 2021-01-25
- Volume
- 42
- Issue
- 4
- Pages
- 436-456
- ISSN
- 0163-769X (ISSN-L)
- 1945-7189
- PMC
- PMC8284618
- OpenAlex
- W3124550675
- Cited by
- 247
- References
- 162
- Citations by year
- 2026: 47 · 2025: 59 · 2024: 60 · 2023: 36 · 2022: 32 · 2021: 13
- FWCI
- 4.70
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Endocrine Reviews (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- NORA - Norwegian Open Research Archives (submittedVersion, cc-by-nc-nd)
- Funders
- Leibniz Institute for Farm Animal Biology
- 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 › Muscle Physiology and Disorders
- Keywords
- FNDC5, irisin, myokines, physical activity, white adipose tissue browning, ectodomain shedding, start codon mutation, bone remodeling, Alzheimer's disease, adipose tissue metabolism
- MeSH terms
- Adipose Tissue, Animals, Biology, Fibronectins, Humans, Muscle, Skeletal, Mice, Adipose Tissue, White
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
