FNDC5

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Fibronectin type III domain-containing protein 5, the precursor of irisin, is a protein that is encoded by the FNDC5 gene.[1] Irisin is a cleaved version of FNDC5, named after the Greek messenger goddess Iris.[2]

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.

History

FNDC5 was discovered during a genome search for fibronectin type III domains[3] and independently in a search for peroxisomal proteins.[1][4]

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.[2][5][6][7][8][9][10][11] Others questioned these findings.[1][12][13][14]

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 sequence of irisin, the cleaved and secreted portion of FNDC5, is highly conserved in mammals; the human and murine sequences are identical.[2] However, the start codon of human FNDC5 is mutated to ATA, which causes it to be expressed at only 1% the level of other animals with the normal ATG start. 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.[15]. There is no comparable study of irisin levels in other animals, where the ATG vs ATA start codon would predict a 100x higher concentration.

A difference in the nucleotide sequence of human FNDC5 from that of mouse Fndc5 creates a different initiation codon, potentially generating a protein that begins at methionine-76 (Met-76). A protein initiated at Met-76 would be missing the signal peptide and would be trapped in the cytoplasm. Via mass spectrometry, irisin has been found to circulate in humans in levels similar to other key hormones, such as insulin.[15].

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.[2][7] Due to its production through a mechanism initiated by muscular contraction, irisin has been classified as a myokine.[16]

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.[5][6] However this proposal has been challenged[17] because FNDC5 is upregulated only in highly active elderly humans.[12]

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.[18]

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.[19][20][unreliable medical source]

See also

References

  1. ↑ 1.0 1.1 1.2 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.
  2. ↑ 2.0 2.1 2.2 2.3 Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Boström EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Højlund K, Gygi SP, Spiegelman BM (January 2012). "A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis". Nature. 481 (7382): 463–8. doi:10.1038/nature10777. PMC 3522098. PMID 22237023.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 5.0 5.1 Courage KH. "Newly Discovered Hormone Boosts Effects of Exercise, Could Help Fend Off Diabetes". Observations. Scientific American. Retrieved January 12, 2012.
  6. ↑ 6.0 6.1 Park A (April 8, 2009). "Brown Fat: A Fat That Helps You Lose Weight?". Health & Family. Time Magazine. Retrieved January 12, 2012.
  7. ↑ 7.0 7.1 Reynolds G (January 11, 2012). "Exercise Hormone May Fight Obesity and Diabetes". Well. New York Times. Retrieved January 12, 2012.
  8. ↑ Zhang Y, Li R, Meng Y, Li S, Donelan W, Zhao Y, Qi L, Zhang M, Wang X, Cui T, Yang LJ, Tang D (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.
  9. ↑ Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, Lin JD, Greenberg ME, Spiegelman BM (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.
  10. ↑ Wu J, Boström P, Sparks LM, Ye L, Choi JH, Giang AH, Khandekar M, Virtanen KA, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt WD, Hoeks J, Enerbäck S, Schrauwen P, Spiegelman BM (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.
  11. ↑ Zhang Y, Xie C, Wang H, Foss RM, Clare M, George EV, Li S, Katz A, Cheng H, Ding Y, Tang D, Reeves WH, Yang LJ (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.
  12. ↑ 12.0 12.1 Timmons JA, Baar K, Davidsen PK, Atherton PJ (August 2012). "Is irisin a human exercise gene?". Nature. 488 (7413): E9–10, discussion E10-1. doi:10.1038/nature11364. PMID 22932392.
  13. ↑ Albrecht E, Norheim F, Thiede B, Holen T, Ohashi T, Schering L, Lee S, Brenmoehl J, Thomas S, Drevon CA, Erickson HP, Maak S (2015). "Irisin - a myth rather than an exercise-inducible myokine". Scientific Reports. 5: 8889. doi:10.1038/srep08889. PMC 4352853. PMID 25749243.
  14. ↑ Raschke S, Elsen M, Gassenhuber H, Sommerfeld M, Schwahn U, Brockmann B, Jung R, Wisløff U, Tjønna AE, Raastad T, Hallén J, Norheim F, Drevon CA, Romacho T, Eckardt K, Eckel J (2013). López-Lluch G, ed. "Evidence against a beneficial effect of irisin in humans". PLoS One. 8 (9): e73680. doi:10.1371/journal.pone.0073680. PMC 3770677. PMID 24040023.
  15. ↑ 15.0 15.1 Jedrychowski MP, Wrann CD, Paulo JA, Gerber KK, Szpyt J, Robinson MM, Nair KS, Gygi SP, Spiegelman BM (October 2015). "Detection and Quantitation of Circulating Human Irisin by Tandem Mass Spectrometry". Cell Metabolism. 22 (4): 734–40. doi:10.1016/j.cmet.2015.08.001. PMC 4802359. PMID 26278051.
  16. ↑ 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.
  17. ↑ Servick K (March 2015). "Biomedicine. Woes for 'exercise hormone'". Science. 347 (6228): 1299. doi:10.1126/science.347.6228.1299. PMID 25792309.
  18. ↑ Reynolds G (2016-10-12). "How Exercise May Turn White Fat Into Brown". The New York Times. ISSN 0362-4331. Retrieved 2016-10-13.
  19. ↑ "A molecule that helps the 'exercise hormone' do its work". Nature. 2018-12-13. Retrieved 2018-12-21.
  20. ↑ Colaianni G, Cuscito C, Mongelli T, Pignataro P, Buccoliero C, Liu P, Lu P, Sartini L, Di Comite M, Mori G, Di Benedetto A, Brunetti G, Yuen T, Sun L, Reseland JE, Colucci S, New MI, Zaidi M, Cinti S, Grano M (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. doi:10.1073/pnas.1516622112. PMC 4593131. PMID 26374841.
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