FNDC5

History

FNDC5 was first discovered in 2002 during a genome search for fibronectin type III domains and independently, in a search for peroxisomal proteins.

The ectodomain was proposed to be cleaved to give a soluble peptide hormone named irisin. Separately it was proposed that irisin is secreted from muscle in response to exercise, and may mediate some beneficial effects of exercise in humans and the potential for generating weight loss and blocking diabetes has been suggested. Others questioned these findings. A 2021 review highlights new discoveries of irisin in brain function and bone remodeling, but criticizes all studies using commercial antibody assays to measure irisin concentrations. It also raises a question of how an exercise hormone could arise in evolution. Shortly afterwards, a study using FNDC5 knock-out mice as well as artificial elevation of circulating irisin levels showed that irisin confers beneficial cognitive effects of physical exercise and that it can serve an exercise mimetic in mice. This regulatory system is therefore investigated for potential interventions to improve cognitive function or alleviate Alzheimer's disease.

Biosynthesis and secretion

The FNDC5 gene encodes a prohormone, a single-pass type I membrane protein (human, 212 amino acids; mouse and rat, 209 amino acids) that is upregulated by muscular exercise and undergoes post-translational processing to generate irisin. The sequence of the protein includes a signal peptide, a single fibronectin type III domain, and a C-terminal hydrophobic domain that is anchored in the cell membrane.

The production of irisin is similar to the shedding and release of other hormones and hormone-like polypeptides, such as epidermal growth factor and TGF alpha, from transmembrane precursors. After the N-terminal signal peptide is removed, the peptide is proteolytically cleaved from the C-terminal moiety, glycosylated and released as a hormone of 112 amino acids (in human, amino acids 32–143 of the full-length protein; in mouse and rat, amino acids 29–140) that comprises most of the FNIII repeat region. The protease/enzyme responsible for the cleavage of FNDC5 to its secreted form, irisin, has not been identified.

The sequence of irisin is highly conserved in mammals; the human and murine sequences are identical. However, the start codon of human FNDC5 is mutated to ATA. This causes human FNDC5 to be potentially expressed in two versions:

• The full-length version with an ATA start, which is transcribed at only 1% the level of other animals with the normal ATG start.
• A severely truncated version beginning at methionine-76 (Met-76). This version has no predicted signal peptide required for transport out of cytoplasm.

A mass spectrometry study reported irisin levels ~3 ng/ml in human plasma, a level on par with other key human hormones, such as insulin. The same study reports that the main form in plasma is the ATA form, as expected for signal peptide presence. There is no comparable study of irisin levels in other animals.

In a more recent study, Witmer et al. provide complementary genomic and molecular evidence to demonstrate that Fndc5 (irisin myokine precursor protein) is translated in humans and mice from an overlooked upstream ATG start codon. These findings lend further support to the likely existence of irisin in humans, revealing more plausible mechanisms of Fndc5 protein translation and processing as compared to possible expression from an inefficient mutated ATA start codon.

Function

Exercise causes increased expression in muscle of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1alpha), which is involved in adaptation to exercise. In mice, this causes production of the FNDC5 protein which is cleaved to give a new product irisin.

Tissues

Fat

Based on the findings that FNDC5 induces thermogenin expression in fat cells, overexpression of FNDC5 in the liver of mice prevents diet-induced weight gain, and FNDC5 mRNA levels are elevated in human muscle samples after exercise, it has been proposed that irisin promotes the conversion of white fat to brown fat in humans, which would make it a health-promoting hormone. While this proposal has been challenged by evidence finding FNDC5 is upregulated only in highly active elderly humans, more recent literature has supported the hypothesis of FNDC5 and irisin having a necessary role in exercise related benefits.

Bones

In mice, irisin released from skeletal muscle during exercise acts directly on bone by increasing cortical bone mineral density, bone perimeter and polar moment of inertia. Irisin regulates bone remodeling and bone metabolism in animal models and humans.

Cognitive effects

Irisin was shown to be a critical regulator of beneficial cognitive effects of physical exercise in rodents.

Molecular interactions

FNDC5 is known to interact with various different molecules. In exercise related effects, PGC-1alpha induces FNDC5 gene expression through ERRα availability and that exercise leads to increased transcription of Pgc-1α and Errα, thus increased transcription of Fndc5. Additionally, FNDC5 is a positive regulator of BDNF expression and can influence BDNF expression in the brain even when peripherally delivered by adenoviral vectors.

Irisin promotes conversion of white adipose tissue (WAT) to brown adipose tissue (BAT) by increasing UCP1 expression. A 2016 in vitro study of white and brown fat cell tissue found dose-related upregulation of a protein called UCP1 that contributes to the browning of white fat and found other markers that would indicate that the white cells were browning and that fat cells were more metabolically active. Many of the stem cells became a type of cell that matures into bone. The tissue treated with irisin produced about 40 percent fewer mature fat cells.

Irisin also interacts with BDNF in terms of regulating its levels in the brain. In a recent study, expression of BDNF in the primary hippocampal nerve cells was observed to decrease as glucose concentration and glucose exposure time increased, or in the diabetic rat conditions. The vitality of these primary hippocampal nerve cells from diabetic rats was markedly decreased when BDNF levels were low but improved following irisin treatment. Thus, irisin was found to positively regulate the expression of BDNF and negatively influence the levels of GHbA1c (human glycated hemoglobin A1c) and AGEs, suggesting that irisin influences cognitive dysfunction in rats with type 2 diabetes by regulating the expression of BDNF and glycometabolism. It appears that these proteins are connected and related to each other in terms of cardiovascular/metabolic diseases, such as hypertension and diabetes.

References

References

1. (October 2013). "Irisin and FNDC5 in retrospect: An exercise hormone or a transmembrane receptor?". Adipocyte.
2. (June 2020). "Impacts of rat hindlimb Fndc5/irisin overexpression on muscle and adipose tissue metabolism". American Journal of Physiology. Endocrinology and Metabolism.
3. (January 2012). "A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis". Nature.
4. (September 2002). "Frcp1 and Frcp2, two novel fibronectin type III repeat containing genes". Gene.
5. (June 2002). "Mouse PeP: a novel peroxisomal protein linked to myoblast differentiation and development". Developmental Dynamics.
6. "Newly Discovered Hormone Boosts Effects of Exercise, Could Help Fend Off Diabetes". [[Scientific American]].
7. (April 8, 2009). "Brown Fat: A Fat That Helps You Lose Weight?".
8. (January 11, 2012). "Exercise Hormone May Fight Obesity and Diabetes". [[The New York Times]].
9. (February 2014). "Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling". Diabetes.
10. (November 2013). "Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway". Cell Metabolism.
11. (July 2012). "Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human". Cell.
12. (August 2016). "Irisin exerts dual effects on browning and adipogenesis of human white adipocytes". American Journal of Physiology. Endocrinology and Metabolism.
13. (August 2012). "Is irisin a human exercise gene?". Nature.
14. (March 2015). "Irisin – a myth rather than an exercise-inducible myokine". Scientific Reports.
15. (2013). "Evidence against a beneficial effect of irisin in humans". PLOS ONE.
16. (July 2021). "Progress and Challenges in the Biology of FNDC5 and Irisin". Endocrine Reviews.
17. "The hormone irisin is found to confer benefits of exercise on cognitive function". medicalxpress.com.
18. (August 25, 2021). "How Exercise May Help Keep Our Memory Sharp". The New York Times.
19. (August 2021). "Exercise hormone irisin is a critical regulator of cognitive function". Nature Metabolism.
20. (October 2015). "Detection and Quantitation of Circulating Human Irisin by Tandem Mass Spectrometry". Cell Metabolism.
21. (May 2024). "Fndc5 is translated from an upstream ATG start codon and cleaved to produce irisin myokine precursor protein in humans and mice". Cell Metabolism.
22. (October 2008). "Muscle as an endocrine organ: focus on muscle-derived interleukin-6". Physiological Reviews.
23. (May 2019). "Fndc5 loss-of-function attenuates exercise-induced browning of white adipose tissue in mice". FASEB Journal.
24. (March 2015). "Biomedicine. Woes for 'exercise hormone'". Science.
25. (September 2015). "The myokine irisin increases cortical bone mass". Proceedings of the National Academy of Sciences of the United States of America.
26. (December 2018). "Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors". Cell.
27. (May 2019). "Irisin and Bone: From Preclinical Studies to the Evaluation of Its Circulating Levels in Different Populations of Human Subjects". Cells.
28. (February 2019). "Irisin regulates the expression of BDNF and glycometabolism in diabetic rats". Molecular Medicine Reports.