Cited by 612Adipose Tissue and MetabolismAdipokines, Inflammation, and Metabolic DiseasesExercise and Physiological Responses

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FNDC5/Irisin Is Not Only a Myokine but Also an Adipokine

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Roca-Rivada, Arturo, Castelao, Cecilia, Senin, Lucía L., Landrove, María O., Baltar, Javier, Crujeiras, Ana Belén, Seoane, Luisa María, Casanueva, Felipe F., Pardo, María·2013·PLoS ONE

DOI 10.1371/journal.pone.0060563PMC PMC3623960

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Abstract

Exercise provides clear beneficial effects for the prevention of numerous diseases. However, many of the molecular events responsible for the curative and protective role of exercise remain elusive. The recent discovery of FNDC5/irisin protein that is liberated by muscle tissue in response to exercise might be an important finding with regard to this unsolved mechanism. The most striking aspect of this myokine is its alleged capacity to drive brown-fat development of white fat and thermogenesis. However, the nature and secretion form of this new protein is controversial. The present study reveals that rat skeletal muscle secretes a 25 kDa form of FNDC5, while the 12 kDa/irisin theoretical peptide was not detected. More importantly, this study is the first to reveal that white adipose tissue (WAT) also secretes FNDC5; hence, it may also behave as an adipokine. Our data using rat adipose tissue explants secretomes proves that visceral adipose tissue (VAT), and especially subcutaneous adipose tissue (SAT), express and secrete FNDC5. We also show that short-term periods of endurance exercise training induced FNDC5 secretion by SAT and VAT. Moreover, we observed that WAT significantly reduced FNDC5 secretion in fasting animals. Interestingly, WAT of obese animals over-secreted this hormone, which might suggest a type of resistance. Because 72% of circulating FNDC5/irisin was previously attributed to muscle secretion, our findings suggest a muscle-adipose tissue crosstalk through a regulatory feedback mechanism.

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Figure 1 Muscle and adipose tissue sample viability and FNDC5 secretion characterization. The presence of IL-6 and adiponectin in muscle (oxidative-soleus and glycolytic-gastrocnemius) and adipose tissue (subcutaneous and visceral) secretomes assessed by western blot are shown in corresponding histograms for band quantification (A and B). PGC1α expression was tested in the same samples by real-time PCR (C and D). The presence of whole FNDC5 (E) and the soluble form of irisin (F) in muscle and adipose tissues are shown in representative images. Histograms of the band quantification from at least 3 independent experiments are shown, and significance is indicated with regard to the control soleus (*p<0.05; **p<0.01) or towards its own tissue control (#p<0.05) (G). CONT: control ad libitum animals; 1 and 3 W: 1 and 3 weeks of exercise training.CC BY · PubMed Central

Figure 2 Adipose tissue secretion of FNDC5/irisin. FNDC5/irisin secretion was assessed in adipose tissue secretomes from SAT, VAT and BAT under ad libitum conditions (A); in SAT and VAT secretomes from animals after one and three weeks of exercise training (B); and in SAT, VAT and BAT from animals with 36-h food restriction or re-feed after 15 minutes (C). FNDC5/irisin SAT and VAT secretion from the DIO and Zucker animal models and anorexic animals are also shown (D, E). Irisin circulating levels for all previous situations are shown taking the most intense band at 25 kDa (F). Representative images of western blots and histograms of band quantifications from at least 3 independent experiments are shown. The results are represented as percentages with regard to each control as well as significance. In the situation of 3 weeks of exercise, results are compared with 1 week of exercise (*p<0.05; **p<0.01). SAT: subcutaneous adipose tissue; VAT: visceral adipose tissue; BAT: brown adipose tissue; DIO: diet induced obesity; CDIO: control DIO; CZ (fa/-): control Zucker; Zucker: fa/fa; CONT: control; EXER: exercise; CABA: control ABA; ABA: activity based anorexia.CC BY · PubMed Central

Figure 3 Adipose tissue expression of FNDC5. FNDC5 expression was assessed in whole adipose tissue using QRT-PCR and western blot in the same secretion study samples shown in Figure 2. Representative images of western blots and histograms of band quantification towards GAPDH from at least 3 independent experiments are shown. Significant protein results are represented as percentages with regard to each control as well as statistically significance (*p<0.05; **p<0.01). QRT-PCR results are shown as arbitrary units and compared with each control (*p<0.05). SAT: subcutaneous adipose tissue; VAT: visceral adipose tissue; BAT: brown adipose tissue; DIO: diet induced obesity; CDIO: control DIO; CZ (fa/-): control Zucker; Zucker: fa/fa; CONT: control; EXER: exercise; CABA: control ABA; ABA: activity based anorexia.CC BY · PubMed Central

Figure 4 UCP1 detection in adipose tissue. Representative western blot images of UCP1 for SAT, VAT and VAT under ad libitum condition and after 3 weeks of exercise are shown (A); UCP1 expression in SAT and VAT among anorexic and control counterparts is shown (B). Histograms of band quantification from at least 3 independent experiments are shown in those cases in which bands exist. Significant protein results are shown as percentages compared with controls in A and with regard to EXER in B (*p<0.05; **p<0.01).CC BY · PubMed Central

Figure 5 Adipose tissue expression of PGC1α. PGC1α expression was assessed in whole adipose tissue using western blot in the same secretion study samples shown in Figure 2. Representative images of western blots and histograms of band quantification towards GAPDH from at least 3 independent experiments are shown. Significant protein results are represented as percentages with regard to each control (*p<0.05). SAT: subcutaneous adipose tissue; VAT: visceral adipose tissue; BAT: brown adipose tissue; DIO: diet induced obesity; CDIO: control DIO; CZ (fa/-): control Zucker; Zucker: fa/fa; CONT: control; EXER: exercise; CABA: control ABA; ABA: activity based anorexia.CC BY · PubMed Central

Figure 6 Mature adipocytes in rats and human adipose tissue secrete FNDC5. The occurrence of FNDC5 in rat and human adipocytes as well as SVCs secretomes (A); in differentiated and non-differentiated 3T3-L1 cell secretomes (B); and in human subcutaneous and visceral adipose tissues and secretomes (C).CC BY · PubMed Central

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1 retracted

RETRACTED: Increased muscle PGC-1α expression protects from sarcopenia and metabolic disease during aging
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Background
Investigation of Irisin Level in Brucella Patients
Algül, Ş., Şenol, F. F., Uğraş, S., Esmer, F., Kara, M., Ekici, P. T., & Özçelik, O. (2021) · Eastern Journal Of Medicine · doi:10.5505/ejm.2021.70431 · Cited by 1
“Irisin, a newly discovered hormone, is an exercise-induced peptide secreted from myocytes and adipocytes (13, 14 15).”
Anadolu Merinoslarında İrisin Hormon Yanıtı Üzerine Bazı Fizyolojik Parametrelerin Etkisi
Bayraktar, B., & Tekçe, E. (2021) · Etlik Veteriner Mikrobiyoloji Dergisi · doi:10.35864/evmd.954977 · Cited by 1
The colors of adipose tissue and the relationship with irisin
Robledo, A., García, B. C. S., Luqueño, E., Mendieta-Zerón, H., Basurto, L., & Oros‐Pantoja, R. (2023) · Cirugía y Cirujanos (English Edition) · doi:10.24875/cirue.m22000180 · Cited by 1
Examination of the Relationship Between Intermittent Fasting and Irisin Levels in Rats Fed on a High-Fat Diet
GÜNBATAR, N., & Bulduk, B. (2023) · Eastern Journal Of Medicine · doi:10.5505/ejm.2023.81236 · Cited by 1
RS3480 Polymorphism of FNDC5/Irisin Is Associated with Type 2 Diabetes Mellitus in Maya-Mestizo Women
Canto‐Cetina, T., Silva-Nicanor, D., Coral‐Vázquez, R. M., Cano-Martínez, L. J., & Canto, P. (2023) · Metabolic Syndrome and Related Disorders · doi:10.1089/met.2023.0042 · Cited by 1
“11 It has been described that irisin stimulates the conversion of the white adipose tissue to brown adipose tissue by upregulating the expression of UCP1, which leads to an increase in energy expenditure.”
Effects of high calorie dietary nutrition and exercise on energy metabolism parameters in obese Wistar albino rats
ÇAKIR, S., & Demirtaş, Y. (2023) · Çukurova medical journal (Online)/Çukurova medical journal · doi:10.17826/cumj.1365921 · Cited by 1
Exploring the role of irisin as a potential biomarker in adolescents and young adults with polycystic ovarian syndrome
Majeed, S., Moin, H., Shafi, R., Fatima, S., Zahra, T., & Zafar, S. (2024) · Women s Health · doi:10.1177/17455057241302559 · Cited by 1
Role of irisin in physical activity, sarcopenia-associated type 2 diabetes, and cardiovascular complications
Berković, M. C., Cigrovski, V., & Ružić, L. (2025) · World Journal of Methodology · doi:10.5662/wjm.v15.i4.105462 · Cited by 4
“…measurement of irisin concentration is still challenging and faces many discrepancies related to the methodology used (for example tandem mass spectrometry vs ELISA)[29], human studies have consistently shown lower irisin levels in sera of diabetic patients compared to healthy controls[20,30-32].”
Acute Sprint Interval Exercise Induces a Greater FGF-21 Response in Comparison to Work-Matched Continuous Exercise
Segsworth, B. M. (2015) · Scholarship@Western (Western University) · Cited by 1
Irisin: A bright or a dark future?
Pereira, A., Costa-Pinho, A., Carvalho, D. M., Maia, J. C., & Freitas, P. (2019) · Revista Portuguesa de Endocrinologia Diabetes e Metabolismo · doi:10.26497/ar180091 · Cited by 1
Effects of aerobic exercise on the expressions of skeletal muscle fiber type-related genes and FNDC-5 in high-fat diet-induced obese rats
Jeon, Y., Ha, K., Seo, D. Y., Yeo, J. Y., Choi, S. J., & Han, J. (2017) · IJASS(International Journal of Applied Sports Sciences) · doi:10.24985/ijass.2017.29.1.42 · Cited by 1
AB0347 Evaluation of the impact of rheumatoid arthritis on sexual function
Brahem, M., Hachfi, H., Hammouda, S. B., Haddada, I., Maraoui, M., Jguirim, M., & Younes, M. B. (2017) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2017-eular.5298 · Cited by 1
Evaluation of structural-functional changes of the left ventricular myocardium in patients with arterial hypertension and obesity by the level of irisin
Shaparenko, О. V., Kravchun, P. H., Кравчун, П. П., Kadykova, O. I., & Lisova, H. (2019) · Zaporozhye Medical Journal · doi:10.14739/2310-1210.2019.1.155783 · Cited by 1
Effect of Adipose Tissue-Derived Stem Cell Transplantation and Six Weeks of Aerobic Exercise on FNDC5 and Irisin Levels in Streptozotocin-Induced Diabetic Rats
nasiraey, M., Chashmi, A. J., & Hashemvarzi, S. A. (2020) · Medical Laboratory Journal · doi:10.52547/mlj.14.6.34 · Cited by 1
Irizin: a new myokine and its effect on metabolism
Prylutska, V. A., Solntsava, A., & Piskun, T. A. (2021) · Ukrainian Journal of Pediatric Endocrinology · doi:10.30978/ujpe2021-1-17 · Cited by 1
Potential Role of Novel Myokine in Rats-Induced Metabolic Syndrome
(2021) · Biointerface Research in Applied Chemistry · doi:10.33263/briac123.33053315 · Cited by 1
MYOKINE IRISIN AND ITS METABOLIC ROLE ON TRICHINELLA SPIRALIS IN EXPERIMENTALLY INFECTED MURINE MODEL
Beshay, E. V. N., & Mostafa, O. (2023) · Journal of the Egyptian Society of Parasitology · doi:10.21608/jesp.2023.312176 · Cited by 1
Low serum irisin levels in newly diagnosed patients with type 2 diabetes mellitus: a meta-analysis
Nurcahya, I. G. N. M., Paramitha, A. A. P., Putrawan, I. B. I. W., & Wulandari, D. C. (2023) · Intisari Sains Medis · doi:10.15562/ism.v14i1.1587 · Cited by 1
Mechanisms Mediating Beneficial Effects of Eicosapentaenoic Acid (EPA) in Insulin Resistance and Obesity: Studies in Muscle
Aljawadi, A. (2013) · ThinkTech (Texas Tech University) · Cited by 1
Iryzyna - nowy mediator homeostazy energetycznej Irisin - a new mediator of energy homeostasis
Daroszewski, J. (2015)
Engineering Irisin for Understanding Its Benefits to Obesity
Ding, Y. (2016)
Characterization of the role of Irisin in skeletal muscle growth and repair
Reza, M. M. (2017) · doi:10.32657/10356/72482
AB0345 Psychiatric disorders related to hyperleptinemia and rheumatoid arthritis clinical activity measured by das28
Mercado, M. V.-D., Rodrígez-Ramírez, A.-M., Chavarría-Ávila, E., Sandoval-García, F., Martin-Marquez, B.-T., Navarro-Hernandez, R.-E., Corona-Meraz, F., & Gómez-Bañuelos, E. (2017) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2017-eular.6808
AB0348 Sleep disorders in patients with rheumatoid arthritis
Brahem, M., Hammouda, S. B., Hachfi, H., Maraoui, M., Haddada, I., Jguirim, M., & Younes, M. B. (2017) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2017-eular.5251
AB0350 Functional disability measured by health assessment questionnaire (HAQ) correlates with disease activity in elderly rheumatoid arthritis patients
Kanıtez, N. A., Pehlivan, Ö., Omma, A., Sandıkçı, S. C., Oner, S. Y., Beş, C., & Çelik, S. (2017) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2017-eular.6662
Is there a relationship between delivery mode and serum irisin levels in pregnant women?
Haberal, E. T., Ulu, İ., Özcan, C., Gök, G. A., Kıran, G., & Kücür, M. (2017) · Journal of Laboratory Medicine · doi:10.1515/labmed-2017-0042
“WAT is also known as an endocrine tissue due to the secretion of leptin [6], ghrelin [7] and irisin [8].”
Background
The Diagnostic Value of Irisin and Visfatin in Experimental Testicular Torsion
Saraç, F., Yeniocak, S., Sarsu, S. B., Yücetaş, E., Olgaç, V., Toptaş, M., & Koldaş, M. (2018) · Medical Bulletin of Haseki · doi:10.4274/haseki.65375
“It is also produced in many tissues including adipose tissue, liver, heart and salivary gland (7-12).”
Background
Novel approaches to white adipose browning and beige adipose activation for the treatment of obesity
Goh, T. (2017) · OpenBU (Boston University)
The Immediate and Extended Effect of Diet and Exercise on Metabolic Flexibility
Allerton, T. D. (2017) · Louisiana State University · doi:10.31390/gradschool_dissertations.4493
What is the Actual Molecular Weight of Irisin Hormone According to Western Blot Analysis?
Uğur, K., & Aydın, S. (2019) · Biochemistry and Modern Applications · doi:10.33805/2638-7735.e103
Meta-analysis of Irisin Levels in Gestational Diabetes Mellitus
Fatima, S. S., Martins, R. S., & Ali, S. A. (2020) · Zenodo (CERN European Organization for Nuclear Research) · doi:10.5281/zenodo.4293996
The Role of Physical Exercise Intesity to Irisin Levels on Overweight and Obese
Abdulloh, I. N., Sugiharto, S., & Rejeki, P. S. (2021) · Folia Medica Indonesiana · doi:10.20473/fmi.v57i4.24268
Blood serum myokine irisin and adipocytokine levels in newborns small for gestational age at birth
Prylutskaya, V. A., Сукало, А. В., & Гончарик, А. В. (2021) · Proceedings of the National Academy of Sciences of Belarus Medical series · doi:10.29235/1814-6023-2021-18-4-402-412
“[4] продемонстрировали, что у иризина, являющегося адипомиокином, который обладает важными аутокринными и эндокринными функциями, имеются особенности секреции в зависимости от анатомического расположения.”
Influential
Irisin: A small myocin with a wide potential
Almeida, H. M. D. E. S., Freire, E. A., Benitez, L. C., Dias, L. G., da Silveira, M. L. M., de Lira, R. C., & Cavalcanti, R. (2021) · MOL2NET International Conference on Multidisciplinary Sciences (MOL2NET) · doi:10.3390/mol2net-07-09659
Study the association of circulating level of Irisin with the anthropometric and metabolic parameters in normal weight, overweight and obese children
Khalil, L., Botrous, O. E., Mohammed, M. A., & elhassan, G. M. A. (2022) · Egyptian Journal of Medical Research · doi:10.21608/ejmr.2022.232221
“Irisin is produced by human muscles and adipose tissue [23].”
Background
Muscle Hormones
Rodríguez, A. M., Bonet, M. L., & Ribot, J. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-813814-4.00026-2
Irisin
Ohtaki, H. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-820649-2.00151-0
Physiological Effects of Irisin and its Research Progress
孙, 卓. (2021) · Open Journal of Natural Science · doi:10.12677/ojns.2021.91018
Egzersiz, İrisin ve Obezite
Öner, S., & Yasul, Y. (2022) · Gaziantep Üniversitesi Spor Bilimleri Dergisi · doi:10.31680/gaunjss.1119354
Evaluating the Effect of Irisin on Obesity-Concerning Physical Activity
Oral, O., Tatlıbal, P., & Stavropoulou, E. (2022) · Journal of Endocrinology Research · doi:10.30564/jer.v4i2.4955
“And research on adults demonstrated that FNDC5/irisin secretion increases after short periods of endurance training ([16]).”
Background
Effects of Resistance Exercise and Fermented Soybean Intake on Protein Expression Markers Related to Browning of White Adipose Tissue in Diet-induced Obese Rats
Kim, Y., Lee, G., Yoon, J., & Kim, K. (2023) · Exercise Science · doi:10.15857/ksep.2023.00374
“FNDC5 is a precursor of irisin and acts as a key factor in the thermogenesis and browning of WAT [33].”
Background
Respostas do treinamento combinado sobre marcadores inflamatórios, metabólicos, autofágicos e de remodelamento do tecido adiposo em diabéticos tipo 2 com excesso de peso
Bonfante, I. L. P. (2019) · doi:10.47749/t/unicamp.2019.1231335
Can irisin be developed as the molecular evolutionary clock based on the origin and functions?
Chen, J., Guo, L., Wang, C., Peng, P., Wu, J., Zhang, H., Liu, F., & Li, Q. (2024) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2024.114515
The Effect of Whole Body Vibration Exercise Applied at Different Environment Temperatures on Distribution of Irisin Hormone in Muscle TissuePreprint
Özcan, N. T., Demirbağ, E., Başkurt, Z., & TONGAL, A. (2024) · Research Square · doi:10.21203/rs.3.rs-4474286/v1
Incidental physical activity and circulating irisin levels in the adult population: A systematic review and meta-analysis
Feter, N., Cunha, L. L., de Paula, D., Feter, J. S., Caputo, E. L., & Rombaldi, A. J. (2024) · Science & Sports · doi:10.1016/j.scispo.2023.10.005
Irisin Modulates Perivascular Adipose Tissue Structure In Rat Thoracic Aorta
Shatarat, A. T., Shurrab, A. M., Al-lahham, H. M., Tarboush, N. A., Badran, D. H., Salameh, M. A., & Badran, R. (2025) · Morphologie · doi:10.1016/j.morpho.2025.100955
A Cross-sectional Analysis of Serum Irisin Levels in Individuals with Thyroid Dysfunction Compared to the Control Population
Chaudhary, I., Mangala, S. J., Latha, A. T., Ramakrishna, M. P., Thalamati, M., Ugraiah, K., Shukla, N., Seetharama, D. B., & Gupta, V. (2025) · Annals of African Medicine · doi:10.4103/aam.aam_219_25
“[17] In contrast to our study, in which all individuals had developed hypothyroidism without a preexisting thyroiditis phase, this study had a population that had developed hypothyroidism following Hashimoto’s thyroiditis.”
Involvement of irisin in passive blood flow restriction for preventing disuse muscle atrophy in rats
Imano, T., & Nakajima, M. (2025) · Scientific Journal of Sport and Performance · doi:10.55860/llbv4638
“In addition to skeletal muscle, other cells that secrete irisin include cardiac muscle, adipose tissue, pancreas, liver, and brain (Aydin et al.,2014, Roca-Rivada et al.,2013).”
Irisin, a promising adipomyokine, shows low levels in relation to periodontal diseases, unlike visfatin and IL-6 (case-control study)
Salim, F. S., & Saliem, S. S. (2025) · Frontiers in Oral Health · doi:10.3389/froh.2025.1614433
“Once FNDC5 is released, it undergoes cleavage by an unknown protease, creating irisin (31).”

Authors: Roca-Rivada, A., Castelao, C., Senin, L. L., Landrove, M. O., Baltar, J., Crujeiras, A. B., Seoane, L. M., Casanueva, F. F., & Pardo, M.
Affiliations: Instituto de Salud Carlos III (ES)
Complejo Hospitalario Universitario de Santiago (ES)
Corresponding author: Pardo, María
ORCID: Roca-Rivada, Arturo
Baltar, Javier
Casanueva, Felipe F.
Pardo, María
Venue: PLoS ONE
Publisher: Public Library of Science (PLoS)
Published: 2013-04-11
Volume: 8
Issue: 4
Pages: e60563
ISSN: 1932-6203 (ISSN-L)
DOI: 10.1371/journal.pone.0060563
PMC: PMC3623960
OpenAlex: W2008675205
Cited by: 612
References: 42
Citations by year: 2026: 12 · 2025: 35 · 2024: 45 · 2023: 46 · 2022: 51 · 2021: 65 · 2020: 45 · 2019: 42 · 2018: 44 · 2017: 52 · 2016: 55 · 2015: 56 · 2014: 44 · 2013: 19
FWCI: 40.28
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: PLoS ONE (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, other-oa)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
RUNA. Repositorio Institucional del Sergas (Servicio Gallego de Salud (SERGAS)) (submittedVersion, cc-by)
Funders: Instituto de Salud Carlos III (CB06/03, FISP10/00537)
Servicio Gallego de Salud
Topics: Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Health Sciences › Medicine › Physiology (medical) › Exercise and Physiological Responses
Keywords: FNDC5, irisin, adipokines, myokines, white adipose tissue, visceral adipose tissue, subcutaneous adipose tissue, skeletal muscle, endurance training, fasting, obesity, thermogenesis, secretome
MeSH terms: Animals, Fibronectins, Humans, Male, Physical Conditioning, Animal, Immunoblotting, Rats, Sprague-Dawley, Muscle, Skeletal, 3T3-L1 Cells, Mice, Rats, Adipose Tissue, White, Adipokines, Real-Time Polymerase Chain Reaction

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FNDC5/Irisin Is Not Only a Myokine but Also an Adipokine

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