FNDC5 (Irisin)

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A ribbon model of cleaved irisin.

FNDC5 is a transmembrane protein present in cells both within and outside of the central nervous system, with PGC1a (an exercise dependent transcriptional coactivator) dependent expression[1]. It was discovered in 2012 by Bostrom et al.[2], and found to be cleaved into a water soluble protein called irisin which has been detected in both human plasma and CSF[3]. FNDC5 and Irisin have been linked to many peripheral phenomena including brown fat adipogenesis[2] and telomere length maintenance[4], as well as neurological effects such as hippocampal BDNF release.[1] This makes both FNDC5 and irisin key protein targets in future treatment plans for metabolic diseases like obesity, and neurodegenerative diseases such as Alzheimer's Disease. Potential irisin receptors, the downstream effects of irisin, and the effects of membrane bound FNDC5 all require further investigation.



FNDC5 was originally discovered in 2002, by two independent groups[6]. One was conducting a genomic search for fibronectin 3 domain coding genes[7], while the other was searching for proteins which localized in peroxisomes[8]. The localization studies of the latter group are disputed, and it is believed that FNDC5 is actually anchored in the cell membrane[6].
FNDC5 had gone unnoticed until December 2012, when Bostrom et al. discovered its cleavage into a secreted protein which they named irisin[2]. Their findings suggested that its presence in the blood affects glucose homeostasis[2]. This has lead to returned interest in FNDC5 as well as a flurry of papers investigating irisin as a possible treatment for metabolic disorders like obesity and diabetes.


The validity of these early irisin studies has been called into question because the antibody used was marketed to bind to an epitope on the C terminal domain of FNDC5[6], the segment which would remain on the cell membrane after proteolytic cleavage. The same antibody was however shown to bind to the recombinant N terminal domain of FNDC5[9], bringing the true epitope into question. This antibody was later discontinued, and its successor from Sigma-Aldrich was shown to detect irisin in various glycosylation states[9].
The original paper by Bostrom et al. also found an increase in plasma irisin in exercising adults[2]. Other papers published in the same year showed irisin increases in exercising seniors, but not in young adults[10][11]. These studies were all conducted in 2012, so the validity of the antibodies used for detection is questionable, and could have caused detection errors in these experiments.

Molecular Characteristics

FNDC5 is expressed in a PGC1a dependant manner[2]
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FNDC5 is upregulated in mice as PGC1a expression is increased through
a. The use of a viral vector, or b. Exercise.

Irisin release from active myocytes[5]
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A potential pathway for the release of irisin from active myocytes.
Ca2+ influx leads to the creation of PGC1a, which under prolonged exercise
activates the expression of FNDC5. FNDC5 is cleaved by an unknown peptidase
and secreted

FNDC5 expression is believed to be increased through exercise, mediated by the exercise dependent transcriptional co-factor PGC1a. This was originally found using both transgenic mice that overexpressed PGC1a, and wild type mice exercising[2]. Both groups were found to have significantly increased expression of FNDC5 mRNA[2].
The translated FNDC5 protein is known to have a signal sequence, followed by a transmembrane domain and a fibronectin type 3 domain[6]. It is believed to be cleaved in the region between the fibronectin and transmembrane domains by an unknown peptidase[6], such that the fibronectin type 3 domain is secreted. This secreted peptide is irisin, and it is thought to be the link between exercising skeletal muscle and the effects of exercise in other organs. Since its discovery, irisin has been known to travel in plasma[2]. It was recently also found in cerebral spinal fluid[3].



Irisin is believed to act as a cytokine, and FNDC5 as a cell surface receptor, howerver the downstream and cellular effects either protein are very poorly understood.
In their 2013 study, Rana et al. found that serum irisin levels correlated positively with telomere length[4]. The study's authors believe that secreted irisin is the link between caloric restriction and the maintenance of telomere length[4].


FNDC5's role in brown fat adipogenesis[14]
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FNDC5, which is expressed as a result of the PGC1a response to exercise,
is cleaved into irisin and secreted. It acts on white adipose tissue, promoting genes
like UCP1, which create metabolically active brown adipose tissue.

The original discovery of irisin in 2012 detailed its role in brown fat adipogenesis[2]. Indeed, irisin was first discovered after brown fat adipogenesis was stimulted by exposing white fat cells to the culture media of PGC1a overexpressing myocytes[2]. This was followed up by direct application of irisin to white adipocytes in vitro and in vivo, and the detection of PPARa (a peroxisome proliferation inducing receptor) as a downstream target in this adipogenesis pathway[2]. The same study also found that mice given a high fat diet and then treated with irisin showed a decrease in insulin tolerance, as well as weight loss[2]. Taken together, these results sparked an interest in irisin as a potential treatment of obesity and type 2 diabetes. Irisin has gained acceptance as an adipogenesis inducer over the past years since its discovery[12][13], and has also been implicated in promoting myogenic gene expression in cultured human primary cells[13].


Hippocampal mRNA expression in responce to peripheral FNDC5[1]
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FNDC5 was upregulated in murine livers using viral
vectors, and mRNA expression in the hippocampus was quantified
using qPCR. [[[individual:brain-derived-neurotrophic-factor

In a landmark study in 2013, it was demonstrated that exercise increased expression of FNDC5 within a rodent hippocampus, and that PGC1a bound to another transcriptional coactivator, the estrogen-related receptor a, was causally linked to this increase[1]. A particularly astonishing finding was that overexpressed FNDC5 in the livers of live mice increased BDNF levels solely in their hippocampi[1]. This treatment also increased the expression of cFos and several immediate early genes in the hippocampus, indicating increased neuronal firing and synaptic strengthening[1]. This study established FNDC5, a molecule previously thought of as a peripheral effector, as a possible causal agent in the beneficial effects of exercise on learning. Coupled with the previous result of irisin within the central nervous system[3], these results suggest a possible pathway for the neural benefits of exercise.
FNDC5 was also found to be upregulated in neuronal differentiation, as an important protein in the proper maturation of neurons and astrocytes[15]. Mouse FNDC5 knockout embryonic stem cells were found to show diminished expression of neuronal maturity markers after differentiation with retinoic acid, compared to wild type stem cells[15]. In addition, irisin has been shown to have positive effects on neuronal growth[16] when applied in high concentrations. These findings suggest a possible crucial role for irisin in the development of the central nervous system.

A potential pathway for [[[individual:brain-derived-neurotrophic-factor
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This figure was created by Wrann et al., 2013, showing
their hypothesized pathway for FNDC5's role in
exercise mediated neurological benefits.

Future applications in neurodegenerative and metabolic disorders

Given its effects on energy metabolism and insulin sensitivity, irisin has been a highly sought-after molecule for the treatment of obesity and diabetes. Its increased expression in these patients can potentially be a long term cure. Screening for PGC1a or FNDC5 mutations may even yield genetic markers for these diseases.
In terms of neurodegenerative disorders, potential irisin therapies can be used to increase BDNF levels in the brain, and provide a neuroprotective effect to patients of diseases like Parkinson's or Alzheimer's in order to slow cell loss. Such a treatment may even be a viable preventative measure in the genetically predisposed.
Regardless, further research must go into determining the receptors bound by irisin and the downstream pathways it utilizes, in order to better predict its effects as a therapeutic agent. Long term animal studies must be preformed to fully uncover all of the widespread effects of this newly discovered molecule.

1. Wrann, C. D., White, J. P., Salogiannnis, J., Laznik-Bogoslavski, D., Wu, J., Ma, D., e al. Spiegelman, B. M. (2013). Exercise induces hippocampal BDNF through a PGC-1alpha/FNDC5 pathway. Cell Metab, 18(5), 649-659.
2. Bostrom, P., Wu, J., Jedrychowski, M. P., Korde, A., Ye, L., Lo, J. C., et al. Spiegelman, B. M. (2012). A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature, 481(7382), 463-468.
3. Piya, M. K., Harte, A. L., Sivakumar, K., Tripathi, G., Voyias, P. D., James, S., et al. McTernan, P. G. (2014). The Identification of Irisin in Human Cerebrospinal Fluid: Influence of Adiposity, Metabolic Markers and Gestational Diabetes. Am J Physiol Endocrinol Metab.
4. Rana, K. S., Arif, M., Hill, E. J., Aldred, S., Nagel, D. A., Nevill, A., … Brown, J. E. (2014). Plasma irisin levels predict telomere length in healthy adults. Age (Dordr), 36(2), 995-1001.
5. Image source: Weight Loss: A New Star is Irisin. https://www.caymanchem.com/app/template/Article.vm/article/2192
6. Erickson, H. P. (2013). Irisin and FNDC5 in retrospect: An exercise hormone or a transmembrane receptor? Adipocyte, 2(4), 289-293.
7. Teufel, A., Malik, N., Mukhopadhyay, M., & Westphal, H. (2002). Frcp1 and Frcp2, two novel fibronectin type III repeat containing genes. Gene, 297(1-2), 79-83.
8. Ferrer-Martinez, A., Ruiz-Lozano, P., & Chien, K. R. (2002). Mouse PeP: a novel peroxisomal protein linked to myoblast differentiation and development. Dev Dyn, 224(2), 154-167.
9. Bostrom, P. A., Fernandez-Real, J. M., & Mantzoros, C. (2014). Irisin in humans: recent advances and questions for future research. Metabolism, 63(2), 178-180.
10. Timmons, J. A., Baar, K., Davidsen, P. K., & Atherton, P. J. (2012). Is irisin a human exercise gene? Nature, 488(7413), E9-10; discussion E10-11.
11. Huh, J. Y., Panagiotou, G., Mougios, V., Brinkoetter, M., Vamvini, M. T., Schneider, B. E., & Mantzoros, C. S. (2012). 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. Metabolism, 61(12), 1725-1738.
12. Shan, T., Liang, X., Bi, P., & Kuang, S. (2013). Myostatin knockout drives browning of white adipose tissue through activating the AMPK-PGC1alpha-Fndc5 pathway in muscle. FASEB J, 27(5), 1981-1989.
13. Huh, J. Y., Dincer, F., Mesfum, E., & Mantzoros, C. S. (2014). Irisin stimulates muscle growth-related genes and regulates adipocyte differentiation and metabolism in humans. Int J Obes (Lond).
14. Castillo-Quan, J. I. (2012). From white to brown fat through the PGC-1alpha-dependent myokine irisin: implications for diabetes and obesity. Dis Model Mech, 5(3), 293-295.
15. Hashemi, M. S., Ghaedi, K., Salamian, A., Karbalaie, K., Emadi-Baygi, M., Tanhaei, S., … Baharvand, H. (2013). Fndc5 knockdown significantly decreased neural differentiation rate of mouse embryonic stem cells. Neuroscience, 231, 296-304.
16. Moon, H. S., Dincer, F., & Mantzoros, C. S. (2013). Pharmacological concentrations of irisin increase cell proliferation without influencing markers of neurite outgrowth and synaptogenesis in mouse H19-7 hippocampal cell lines. Metabolism, 62(8), 1131-1136.

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