Irisin stimulates muscle growth-related genes and regulates adipocyte differentiation and metabolism in humans
Abstract
Background Irisin is a recently identified exercise-induced myokine suggested to induce browning of white adipocytes. Deficiency of myostatin, and thus stimulation of muscle growth, has also been reported to induce irisin and its precursor FNDC5 expression in muscle and drive the browning of white adipocytes in mice, implying that irisin may be related to muscle growth in addition to its beneficial effects in adipocytes. In humans, the effect of irisin in muscle hypertrophy as well as adipocyte metabolism has not been fully investigated.Methods Primary cultured human myocytes/adipocytes and 3T3-L1 cells were used to examine irisin-regulated gene/protein expression. Lipid accumulation, ATP content, glycolysis, lipolysis and metabolite profile were measured in control and irisin-treated (10 and 50 nM) adipocytes.Results In human myocytes, FNDC5 mRNA and irisin secretion were increased during myogenic differentiation, along with PGC1α and myogenin expression. Irisin treatment significantly increased insulin-like growth factor 1 and decreased myostatin gene expression through ERK pathway. PGC1α4, a newly discovered PGC1α isoform specifically related to muscle hypertrophy, was also upregulated. In human adipocytes, irisin induced uncoupling protein 1 and consequently increased adipocyte energy expenditure, expression of metabolic enzymes and metabolite intermediates, resulting in inhibition of lipid accumulation. Irisin and FNDC5 treatment also reduced preadipocyte differentiation, suggesting an additional mechanism in suppressing fat mass.Conclusions These results suggest that irisin/FNDC5 has a pleiotropic role in muscle and improvement of adipocyte metabolism in humans.
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An inter-myokine axis with irisin and crosstalk with follistatin could represent a mechanism through which myostatin is decreased by exercise.
“The possibility of an inter-myokine axis with irisin [44,49] and crosstalk with follistatin could represent a mechanism through which myostatin is decreased by exercise.”
Exercise-induced reduction of myostatin by irisin reduces availability of myostatin to engage in proinflammatory responses.
“Likewise, exercise-induced reduction of myostatin by irisin [44] (7a) was described to reduce availability of myostatin to engage in proinflammatory responses [116] (7b).”
Irisin inhibits myostatin.
“while irisin exerts a dual effect by also inhibiting myostatin [44] (2b)”
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“Myokines myostatin↔ irisin [44,49] METRNL→ ↑irisin, BAIBA* [92,100] FGF21→ ↑irisin* [43] follistatin→ ↓myostatin [184] SeP→ ↓adiponectin [136], ↓irisin, BAIBA, METRNL (via ↓PGC-1α due to ↓OS)* [50] irisin→ ↑adiponectin [51], ?↓leptin [54,55] IL-15→↑adiponectin [86] BAIBA→ ↑leptin [109] irisin→ ↓TNF-α, IL-1β, IL-6, MCP…”
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- Authors
- Huh, J. Y., Dincer, F., Mesfum, E., & Mantzoros, C. S.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Mantzoros, C S
- Venue
- International Journal of Obesity
- Published
- 2014-03-11
- Volume
- 38
- Issue
- 12
- Pages
- 1538-1544
- ISSN
- 0307-0565 (ISSN-L)
- 1476-5497
- OpenAlex
- W2022352721
- Cited by
- 309
- References
- 33
- Citations by year
- 2026: 15 · 2025: 23 · 2024: 28 · 2023: 30 · 2022: 56 · 2021: 27 · 2020: 24 · 2019: 23 · 2018: 15 · 2017: 25 · 2016: 18 · 2015: 14 · 2014: 11
- FWCI
- 15.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- International Journal of Obesity (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- irisin, FNDC5, myokines, muscle hypertrophy, adipogenesis, adipocyte metabolism, white adipose tissue browning, myostatin, insulin-like growth factor I, ERK signaling, UCP1, energy expenditure, lipid accumulation, preadipocyte differentiation, 3T3-L1 adipocytes
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Fibronectins, Gene Expression Regulation, Humans, Insulin Resistance, RNA, Messenger, Blotting, Western, Biomarkers, Adipocytes, Muscle, Skeletal, Myocytes, Smooth Muscle, 3T3-L1 Cells, Mice
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