FNDC5

Last updated

FNDC5
FNDC5.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases FNDC5 , FRCP2, irisin, Irisin, fibronectin type III domain containing 5
External IDs OMIM: 611906; MGI: 1917614; HomoloGene: 17812; GeneCards: FNDC5; OMA:FNDC5 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

252995

384061

Ensembl

ENSG00000160097

ENSMUSG00000001334

UniProt

Q8NAU1

Q8K4Z2

RefSeq (mRNA)

NM_153756
NM_001171940
NM_001171941

NM_027402

RefSeq (protein)

NP_001165411
NP_001165412
NP_715637

NP_081678

Location (UCSC) Chr 1: 32.86 – 32.87 Mb Chr 4: 129.03 – 129.04 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Fibronectin type III domain-containing protein 5, the precursor of irisin, is a type I transmembrane glycoprotein that is encoded by the FNDC5 gene. [5] [6] [7] Irisin is a cleaved version of FNDC5, named after the Greek messenger goddess Iris. [7]

Contents

Fibronectin domain-containing protein 5 is a membrane protein comprising a short cytoplasmic domain, a transmembrane segment, and an ectodomain consisting of a ~100 kDa fibronectin type III (FNIII) domain. [8]

History

FNDC5 was first discovered in 2002 during a genome search for fibronectin type III domains [9] and independently, in a search for peroxisomal proteins. [5] [10]

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. [7] [11] [12] [13] [14] [15] [16] [17] Others questioned these findings. [5] [18] [19] [20] 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. [21] 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. [22] [23] [24]

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. [8]

The sequence of irisin is highly conserved in mammals; the human and murine sequences are identical. [7] However, the start codon of human FNDC5 is mutated to ATA. This causes human FNDC5 to be potentially expressed in two versions:

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. [8] There is no comparable study of irisin levels in other animals.

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. [7] [13] Due to its production through a mechanism initiated by muscular contraction, irisin has been classified as a myokine. [25]

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. [11] [12] [26] While this proposal has been challenged [27] by evidence finding FNDC5 is upregulated only in highly active elderly humans, [18] more recent literature has supported the hypothesis of FNDC5 and irisin having a necessary role in exercise related benefits. [26] [6]

Bones

In mice, irisin is released from skeletal muscle during exercise acts directly on bone by increasing cortical bone mineral density, bone perimeter and polar moment of inertia. [28] Irisin regulates bone remodeling [29] and bone metabolism in animal models and humans. [30]

Cognitive effects

Irisin was shown to be a critical regulator of beneficial cognitive effects of physical exercise in rodents. [24]

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. [15] Additionally, FNDC5 is a positive regulator of BDNF expression and can influence BDNF expression in the brain even when peripherally delivered by adenoviral vectors. [15]

Irisin promotes conversion of white adipose tissue (WAT) to brown adipose tissue (BAT) by increasing UCP1 expression. [7] 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. [7]

Irisin also interacts with BDNF in terms of regulating its levels in the brain. [15] [31] 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. [31] It appears that these proteins are connected and related to each other in terms of cardiovascular/metabolic diseases, such as hypertension and diabetes.

See also

Related Research Articles

<span class="mw-page-title-main">Leptin</span> Hormone that inhibits hunger

Leptin also obese protein is a protein hormone predominantly made by adipocytes. Its primary role is likely to regulate long-term energy balance.

<span class="mw-page-title-main">Brown adipose tissue</span> Type of adipose tissue

Brown adipose tissue (BAT) or brown fat makes up the adipose organ together with white adipose tissue. Brown adipose tissue is found in almost all mammals.

<span class="mw-page-title-main">Adipose tissue</span> Loose connective tissue composed mostly by adipocytes

Adipose tissue is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and a variety of immune cells such as adipose tissue macrophages. Its main role is to store energy in the form of lipids, although it also cushions and insulates the body.

<span class="mw-page-title-main">Adipocyte</span> Cells that primarily compose adipose tissue, specialized in storing energy as fat

Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. In cell culture, adipocyte progenitors can also form osteoblasts, myocytes and other cell types.

<span class="mw-page-title-main">Adiponectin</span> Mammalian protein found in Homo sapiens

Adiponectin is a protein hormone and adipokine, which is involved in regulating glucose levels and fatty acid breakdown. In humans, it is encoded by the ADIPOQ gene and is produced primarily in adipose tissue, but also in muscle and even in the brain.

<span class="mw-page-title-main">Interleukin 6</span> Cytokine protein

Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the IL6 gene.

<span class="mw-page-title-main">Osteocalcin</span> Mammalian protein found in Homo sapiens

Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein (BGLAP), is a small (49-amino-acid) noncollagenous protein hormone found in bone and dentin, first identified as a calcium-binding protein.

<span class="mw-page-title-main">Perilipin-1</span> Protein in humans

Perilipin, also known as lipid droplet-associated protein, perilipin 1, or PLIN, is a protein that, in humans, is encoded by the PLIN gene. The perilipins are a family of proteins that associate with the surface of lipid droplets. Phosphorylation of perilipin is essential for the mobilization of fats in adipose tissue.

<span class="mw-page-title-main">Agouti-signaling protein</span> Protein-coding gene in the species Homo sapiens

Agouti-signaling protein is a protein that in humans is encoded by the ASIP gene. It is responsible for the distribution of melanin pigment in mammals. Agouti interacts with the melanocortin 1 receptor to determine whether the melanocyte produces phaeomelanin, or eumelanin. This interaction is responsible for making distinct light and dark bands in the hairs of animals such as the agouti, which the gene is named after. In other species such as horses, agouti signalling is responsible for determining which parts of the body will be red or black. Mice with wildtype agouti will be grey-brown, with each hair being partly yellow and partly black. Loss of function mutations in mice and other species cause black fur coloration, while mutations causing expression throughout the whole body in mice cause yellow fur and obesity.

<span class="mw-page-title-main">Follistatin</span> Mammalian protein found in Homo sapiens

Follistatin, also known as activin-bindings protein, is a protein that in humans is encoded by the FST gene. Follistatin is an autocrine glycoprotein that is expressed in nearly all tissues of higher animals.

<span class="mw-page-title-main">CD1D</span> Mammalian protein found in Homo sapiens

CD1D is the human gene that encodes the protein CD1d, a member of the CD1 family of glycoproteins expressed on the surface of various human antigen-presenting cells. They are non-classical MHC proteins, related to the class I MHC proteins, and are involved in the presentation of lipid antigens to T cells. CD1d is the only member of the group 2 CD1 molecules.

<span class="mw-page-title-main">Rev-ErbA alpha</span> Protein-coding gene in the species Homo sapiens

Rev-Erb alpha (Rev-Erbɑ), also known as nuclear receptor subfamily 1 group D member 1 (NR1D1), is one of two Rev-Erb proteins in the nuclear receptor (NR) family of intracellular transcription factors. In humans, REV-ERBɑ is encoded by the NR1D1 gene, which is highly conserved across animal species.

<span class="mw-page-title-main">Adipose triglyceride lipase</span> Mammalian protein found in Homo sapiens

Adipose triglyceride lipase, also known as patatin-like phospholipase domain-containing protein 2 and ATGL, is an enzyme that in humans is encoded by the PNPLA2 gene. ATGL catalyses the first reaction of lipolysis, where triacylglycerols are hydrolysed to diacylglycerols.

A myokine is one of several hundred cytokines or other small proteins and proteoglycan peptides that are produced and released by skeletal muscle cells in response to muscular contractions. They have autocrine, paracrine and/or endocrine effects; their systemic effects occur at picomolar concentrations.

Epigenetics of physical exercise is the study of epigenetic modifications to the cell genome resulting from physical exercise. Environmental factors, including physical exercise, have been shown to have a beneficial influence on epigenetic modifications. Generally, it has been shown that acute and long-term exercise has a significant effect on DNA methylation, an important aspect of epigenetic modifications.

<span class="mw-page-title-main">Erythroferrone</span> Mammalian protein found in Homo sapiens

Erythroferrone is a protein hormone encoded in humans by the ERFE gene. Erythroferrone is produced by erythroblasts, inhibits the production of hepcidin in the liver, and so increases the amount of iron available for hemoglobin synthesis. Skeletal muscle secreted ERFE has been shown to maintain systemic metabolic homeostasis.

<span class="mw-page-title-main">Bone marrow adipose tissue</span>

Bone marrow adipose tissue (BMAT), sometimes referred to as marrow adipose tissue (MAT), is a type of fat deposit in bone marrow. It increases in states of low bone density -osteoporosis, anorexia nervosa/caloric restriction, skeletal unweighting such as that which occurs in space travel, and anti-diabetes therapies. BMAT decreases in anaemia, leukaemia, and hypertensive heart failure; in response to hormones such as oestrogen, leptin, and growth hormone; with exercise-induced weight loss or bariatric surgery; in response to chronic cold exposure; and in response to pharmacological agents such as bisphosphonates, teriparatide, and metformin.

Bruce Michael Spiegelman is an American biochemist and cell biologist. Since 2008, Spiegelman has been the Stanley J. Korsmeyer Professor of Cell Biology and Medicine at the Dana–Farber Cancer Institute and Harvard Medical School, and director of the Center for Metabolism and Chronic Disease at the Dana-Farber.

Hepatokines are proteins produced by liver cells (hepatocytes) that are secreted into the circulation and function as hormones across the organism. Research is mostly focused on hepatokines that play a role in the regulation of metabolic diseases such as diabetes and fatty liver and include: Adropin, ANGPTL4, Fetuin-A, Fetuin-B, FGF-21, Hepassocin, LECT2, RBP4,Selenoprotein P, Sex hormone-binding globulin.

An exerkine is a signaling molecule released in response to exercise that helps mediate systemic adaptations to exercise.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000160097 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000001334 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 Erickson HP (October 2013). "Irisin and FNDC5 in retrospect: An exercise hormone or a transmembrane receptor?". Adipocyte. 2 (4): 289–93. doi:10.4161/adip.26082. PMC   3774709 . PMID   24052909.
  6. 1 2 Farrash W, Brook M, Crossland H, Phillips BE, Cegielski J, Wilkinson DJ, et al. (June 2020). "Impacts of rat hindlimb Fndc5/irisin overexpression on muscle and adipose tissue metabolism". American Journal of Physiology. Endocrinology and Metabolism . 318 (6): E943–E955. doi:10.1152/ajpendo.00034.2020. PMC   7311674 . PMID   32369414.
  7. 1 2 3 4 5 6 7 Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al. (January 2012). "A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis". Nature . 481 (7382): 463–8. Bibcode:2012Natur.481..463B. doi:10.1038/nature10777. PMC   3522098 . PMID   22237023.
  8. 1 2 3 Jedrychowski MP, Wrann CD, Paulo JA, Gerber KK, Szpyt J, Robinson MM, et al. (October 2015). "Detection and Quantitation of Circulating Human Irisin by Tandem Mass Spectrometry". Cell Metabolism. 22 (4): 734–740. doi:10.1016/j.cmet.2015.08.001. PMC   4802359 . PMID   26278051.
  9. ↑ Teufel A, Malik N, Mukhopadhyay M, Westphal H (September 2002). "Frcp1 and Frcp2, two novel fibronectin type III repeat containing genes". Gene . 297 (1–2): 79–83. doi:10.1016/S0378-1119(02)00828-4. PMID   12384288.
  10. ↑ Ferrer-Martínez A, Ruiz-Lozano P, Chien KR (June 2002). "Mouse PeP: a novel peroxisomal protein linked to myoblast differentiation and development". Developmental Dynamics . 224 (2): 154–67. doi: 10.1002/dvdy.10099 . PMID   12112469. S2CID   42445530.
  11. 1 2 Courage KH. "Newly Discovered Hormone Boosts Effects of Exercise, Could Help Fend Off Diabetes". Observations. Scientific American . Retrieved January 12, 2012.
  12. 1 2 Park A (April 8, 2009). "Brown Fat: A Fat That Helps You Lose Weight?". Health & Science. Time . Archived from the original on April 11, 2009. Retrieved January 12, 2012.
  13. 1 2 Reynolds G (January 11, 2012). "Exercise Hormone May Fight Obesity and Diabetes". Well. The New York Times . Retrieved January 12, 2012.
  14. ↑ Zhang Y, Li R, Meng Y, Li S, Donelan W, Zhao Y, et al. (February 2014). "Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling". Diabetes . 63 (2): 514–25. doi: 10.2337/db13-1106 . PMID   24150604.
  15. 1 2 3 4 Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, et al. (November 2013). "Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway". Cell Metabolism . 18 (5): 649–59. doi:10.1016/j.cmet.2013.09.008. PMC   3980968 . PMID   24120943.
  16. ↑ Wu J, Boström P, Sparks LM, Ye L, Choi JH, Giang AH, et al. (July 2012). "Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human". Cell . 150 (2): 366–76. doi:10.1016/j.cell.2012.05.016. PMC   3402601 . PMID   22796012.
  17. ↑ Zhang Y, Xie C, Wang H, Foss RM, Clare M, George EV, et al. (August 2016). "Irisin exerts dual effects on browning and adipogenesis of human white adipocytes". American Journal of Physiology. Endocrinology and Metabolism. 311 (2): E530-41. doi:10.1152/ajpendo.00094.2016. PMID   27436609. S2CID   3433786.
  18. 1 2 Timmons JA, Baar K, Davidsen PK, Atherton PJ (August 2012). "Is irisin a human exercise gene?". Nature. 488 (7413): E9-10, discussion E10-1. Bibcode:2012Natur.488E...9T. doi:10.1038/nature11364. PMID   22932392. S2CID   4415979.
  19. ↑ Albrecht E, Norheim F, Thiede B, Holen T, Ohashi T, Schering L, et al. (March 2015). "Irisin - a myth rather than an exercise-inducible myokine". Scientific Reports . 5: 8889. Bibcode:2015NatSR...5E8889A. doi:10.1038/srep08889. PMC   4352853 . PMID   25749243.
  20. ↑ Raschke S, Elsen M, Gassenhuber H, Sommerfeld M, Schwahn U, Brockmann B, et al. (2013). López-Lluch G (ed.). "Evidence against a beneficial effect of irisin in humans". PLOS One . 8 (9): e73680. Bibcode:2013PLoSO...873680R. doi: 10.1371/journal.pone.0073680 . PMC   3770677 . PMID   24040023.
  21. ↑ Maak, S.; Norheim, F.; Drevon, C. A.; Erickson, H. P. (2021). "Progress and Challenges in the Biology of FNDC5 and Irisin". Endocrine Reviews . 42 (4): 436–456. doi:10.1210/endrev/bnab003. PMC   8284618 . PMID   33493316.
  22. ↑ "The hormone irisin is found to confer benefits of exercise on cognitive function". medicalxpress.com. Retrieved September 21, 2021.
  23. ↑ Reynolds, Gretchen (August 25, 2021). "How Exercise May Help Keep Our Memory Sharp". The New York Times. Retrieved September 21, 2021.
  24. 1 2 Islam, Mohammad R.; Valaris, Sophia; Young, Michael F.; Haley, Erin B.; Luo, Renhao; Bond, Sabrina F.; Mazuera, Sofia; Kitchen, Robert R.; Caldarone, Barbara J.; Bettio, Luis E. B.; Christie, Brian R.; Schmider, Angela B.; Soberman, Roy J.; Besnard, Antoine; Jedrychowski, Mark P.; Kim, Hyeonwoo; Tu, Hua; Kim, Eunhee; Choi, Se Hoon; Tanzi, Rudolph E.; Spiegelman, Bruce M.; Wrann, Christiane D. (August 2021). "Exercise hormone irisin is a critical regulator of cognitive function". Nature Metabolism . 3 (8): 1058–1070. doi:10.1038/s42255-021-00438-z. ISSN   2522-5812. PMC   10317538 . PMID   34417591. S2CID   237254736.
  25. ↑ Pedersen BK, Febbraio MA (October 2008). "Muscle as an endocrine organ: focus on muscle-derived interleukin-6". Physiological Reviews. 88 (4): 1379–406. doi:10.1152/physrev.90100.2007. PMID   18923185.
  26. 1 2 Xiong Y, Wu Z, Zhang B, Wang C, Mao F, Liu X, et al. (May 2019). "Fndc5 loss-of-function attenuates exercise-induced browning of white adipose tissue in mice". The FASEB Journal . 33 (5): 5876–5886. doi: 10.1096/fj.201801754RR . PMID   30721625. S2CID   73444056.
  27. ↑ Servick K (March 2015). "Biomedicine. Woes for 'exercise hormone'". Science . 347 (6228): 1299. doi: 10.1126/science.347.6228.1299 . PMID   25792309.
  28. ↑ Colaianni G, Cuscito C, Mongelli T, Pignataro P, Buccoliero C, Liu P, et al. (September 2015). "The myokine irisin increases cortical bone mass". Proceedings of the National Academy of Sciences of the United States of America . 112 (39): 12157–62. Bibcode:2015PNAS..11212157C. doi: 10.1073/pnas.1516622112 . PMC   4593131 . PMID   26374841.
  29. ↑ Kim H, Wrann CD, Jedrychowski M, Vidoni S, Kitase Y, Nagano K, et al. (December 2018). "Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors". Cell. 175 (7): 1756–1768.e17. doi:10.1530/ey.16.15.15. PMC   6298040 . PMID   30550785.
  30. ↑ Colaianni G, Sanesi L, Storlino G, Brunetti G, Colucci S, Grano M (May 2019). "Irisin and Bone: From Preclinical Studies to the Evaluation of Its Circulating Levels in Different Populations of Human Subjects". Cells. 8 (5): 451. doi: 10.3390/cells8050451 . PMC   6562988 . PMID   31091695.
  31. 1 2 Huang L, Yan S, Luo L, Yang L (February 2019). "Irisin regulates the expression of BDNF and glycometabolism in diabetic rats". Molecular Medicine Reports . 19 (2): 1074–1082. doi:10.3892/mmr.2018.9743. PMC   6323232 . PMID   30569121.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.