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Cited by 1,040Adipose Tissue and MetabolismAdipokines, Inflammation, and Metabolic DiseasesMuscle Physiology and Disorders

FNDC5 and Irisin in Humans: I. Predictors of Circulating Concentrations in Serum and Plasma and II. mRNA Expression and Circulating Concentrations in Response to Weight Loss and Exercise

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Huh, Joo Young, Panagiotou, Grigorios, Mougios, Vassilis, Brinkoetter, Mary, Vamvini, Maria T., Schneider, Benjamin E., Mantzoros, Christos S.·2012·Metabolism
DOI 10.1016/j.metabol.2012.09.002PMC PMC3614417
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Abstract

Objective In mouse, PGC1-α overexpression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. One prior study has shown that FNDC5 induces browning of subcutaneous fat in mice and mediates beneficial effects of exercise on metabolism, but a more recent study using gene expression arrays failed to detect a robust increase in FNDC5 mRNA in human muscles from exercising subjects. No prior study has reported on the physiological regulation and role of circulating irisin and FNDC5 in humans.Materials/methods A. FNDC5 gene expression studies: We first examined tissue distribution of FNDC5 in humans. B. Cross-sectional studies: Predictors of FNDC5 mRNA expression levels were examined in muscle tissues from 18 healthy subjects with a wide range of BMI. Assays were optimized to measure circulating FNDC5 and irisin levels, and their associations with anthropometric and metabolic parameters were analyzed in two cross-sectional studies that examined 117 middle-aged healthy women and 14 obese subjects, respectively. C. Interventional studies: The effect of weight loss on FNDC5 mRNA and/or circulating irisin levels was examined in 14 obese subjects before and after bariatric surgery. The effect of acute and chronic exercise was then assessed in 15 young healthy adults who performed intermittent sprint running sessions over an 8 week period.Results Tissue arrays demonstrated that in humans, the FNDC5 gene is predominantly expressed in muscle. Circulating irisin was detected in the serum or plasma of all subjects studied, whereas circulating FNDC5 was detected in only a distinct minority of the subjects. Cross-sectional studies revealed that circulating irisin levels were positively correlated with biceps circumference (used as a surrogate marker of muscle mass herein), BMI, glucose, ghrelin, and IGF-1. In contrast, irisin levels were negatively correlated with age, insulin, cholesterol, and adiponectin levels, indicating a possible compensatory role of irisin in metabolic regulation. Multivariate regression analysis revealed that biceps circumference was the strongest predictor of circulating irisin levels underlying the association between irisin and metabolic factors in humans at baseline. Both muscle FNDC5 mRNA levels and circulating irisin levels were significantly downregulated 6 months after bariatric surgery. Circulating irisin levels were significantly upregulated 30 min after acute exercise and were correlated mainly with ATP levels and secondarily with metabolites related to glycolysis and lipolysis in muscle.Conclusions Similar to mice, the FNDC5 gene is expressed in human muscle. Age and muscle mass are the primary predictors of circulating irisin, with young male athletes having several fold higher irisin levels than middle-aged obese women. Circulating irisin levels increase in response to acute exercise whereas muscle FNDC5 mRNA and circulating irisin levels decrease after surgically induced weight loss in parallel to decrease in body mass. Further studies are needed to study the regulation of irisin levels and its physiological effects in humans and to elucidate the mechanisms underlying these effects.

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  • These findings suggest a compensatory mechanism in which adipocyte-derived irisin aims to stimulate brown adipose tissue activity, increase energy expenditure, and counteract insulin resistance.

    “These findings suggest a compensatory mechanism in which adipocyte-derived irisin aims to stimulate brown adipose tissue activity, increase energy expenditure, and counteract insulin resistance [60,61].”

    From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [60]

    The Discussion (page unavailable) suggests that irisin may compensate for deteriorating insulin sensitivity and increase energy use in adipocytes. It does not establish an adipocyte-derived mechanism: it reports FNDC5 expression in fat at about 1/100 of that in muscle and describes irisin’s effect on adipose tissue as probably endocrine. The Introduction and Discussion discuss browning and thermogenesis in subcutaneous white fat, rather than increased activity of existing brown adipose tissue. (LLM, conf=0.88)

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  • In 77 obese prepubertal children aged 4 to 12 years, elevated serum irisin levels and potential irisin resistance were reported in obese participants compared with non-obese controls.

    “A study by Herouvi et al. (2025), involving 77 obese prepubertal children aged 4 to 12 years, reported elevated serum irisin levels and potential irisin resistance in obese participants compared with non-obese controls.”

    From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [60]

    The Methods (§2.2) describe studies of adult women and adults undergoing bariatric surgery, not 77 prepubertal children. The Results (§3.4) discuss adult irisin concentrations and correlations, but do not report a comparison between obese and non-obese children or potential irisin resistance. Searches for Herouvi, the child cohort, and irisin resistance found no matching passage in our copy; page numbers were unavailable. (LLM, conf=0.78)

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  • In diabetic C57BL/6 mice treated with irisin (0.5 mg/kg/day) for two weeks, ex vivo incubation of diabetic aortic segments with irisin (1 μg/mL) significantly reduced levels of oxidative and nitrative stress markers.

    “In diabetic C57BL/6 mice treated with irisin (0.5 mg/kg/day) for two weeks, the ex vivo incubation of diabetic aortic segments with irisin (1 μg/mL) significantly reduced the levels of oxidative and nitrative stress markers.”

    From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [60]

    The Methods (§2.2, page unavailable) describe human studies of circulating irisin, weight loss, and exercise, not treatment of diabetic mice or ex vivo aortic segments. Searches for aortic oxidative and nitrative stress and for the stated irisin doses found no passage addressing the claimed experiment. (LLM, conf=0.78)

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  • These effects are mediated via inhibition of PKC-β/NADPH oxidase and NF-κB/iNOS pathways, resulting in improved endothelial function.

    “These effects are mediated via the inhibition of the protein kinase C beta (PKC-β)/NADPH oxidase and NF-κB/inducible nitric oxide synthase (iNOS) pathways, resulting in improved endothelial function [60].”

    From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [60]

    The Introduction and Discussion describe irisin, exercise, and metabolic effects, but do not address endothelial function or the claimed PKC-β/NADPH oxidase and NF-κB/iNOS pathways. Searches for those pathways and for vascular or endothelial mechanisms found no supporting passage in our copy; page numbers were not available. (LLM, conf=0.76)

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Authors
Huh, J. Y., Panagiotou, G., Mougios, V., Brinkoetter, M., Vamvini, M. T., Schneider, B. E., & Mantzoros, C. S.
Affiliations
  • Beth Israel Deaconess Medical Center (US)
  • Aristotle University of Thessaloniki (GR)
Corresponding author
Mantzoros, Christos S.
ORCID
Venue
Metabolism
Publisher
Elsevier BV
Published
2012-12
Volume
61
Issue
12
Pages
1725-1738
ISSN
0026-0495 (ISSN-L)
DOI
10.1016/j.metabol.2012.09.002
PMC
PMC3614417
OpenAlex
W2076975132
Cited by
1,040
References
31
Citations by year
2026: 39 · 2025: 67 · 2024: 68 · 2023: 58 · 2022: 106 · 2021: 88 · 2020: 76 · 2019: 73 · 2018: 77 · 2017: 74 · 2016: 77 · 2015: 86 · 2014: 87 · 2013: 63 · 2012: 1
FWCI
50.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Diabetes and Digestive and Kidney Diseases (58785, 79929, 81913)
  • Clinical Science Research and Development Service of the VA Office of Research and Development (1I01CX000422-01A1)
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, PGC-1α, weight loss, bariatric surgery, physical activity, sprinting, muscle mass, obesity, circulating hormone levels, mRNA expression, adiponectin, ghrelin, insulin-like growth factor I, insulin, ATP, skeletal muscle, metabolic regulation, sex differences, age differences
MeSH terms
Adenosine Triphosphate, Adult, Cross-Sectional Studies, Female, Fibronectins, Gene Expression Regulation, Glycolysis, Hormones, Humans, Lipolysis, Male, Middle Aged, Obesity, Morbid, RNA, Messenger, Biomarkers, Weight Loss, Exercise, Body Mass Index, Bariatric Surgery, Athletes

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